AIDS and Complementary & Alternative Medicine: Current Science and Practice

CHURCHILL LIVINGSTONE A Harcourt Health Sciences Company The Curtis Center Independence Square West Philadelphia, Pennsylvania 19106-3399

NOTICE Complementary and alternative medicine is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verily the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the editors assume any liability for any injury and/or damage to persons or property arising from this publication.

Publishing Director: John A. Schrefer Associate Editor: Kellie F. Conklin Associate Developmental Editor: Jennifer L. Watrous Project Manager: Karen Edwards Design: Renee Duenow

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE: CURRENT SCIENCE AND PRACTICE

ISBN 0-443-05831-8

Copyright © 2002 by Churchill Livingstone All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. CHURCHILL LIVINGSTONE and the Sail Boat Design are trademarks of Harcourt, Inc., registered in the United States of Amercia and/or other jurisdictions. Printed in the United States of America. Last digit is the print number:

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Contributors

JOHN G. BABISH, PhD Chairperson, BIONEXUS, Ltd Ithaca, New York ANNE E. BELCHER, PhD, RN, AOCN, FAAN Professor and Director, Undergraduate Program Department of Nursing College of Health Professions Thomas Jefferson University Philadelphia, Pennsylvania BARBARA BREWITT, PhD Chief Scientific Officer, Biomed Comm, Inc Visiting StaffScientist, Department of Biological Structure University ofWashington Seattle, Washington CARLO CALABRESE, ND, MPH Research Professor National College of Naturopathic Medicine President, Triangle Research Partners Portland, Oregon BRUNO CHIKLY, MD (France) Laureat of the Medical Faculty of Paris Associate Member of the American Academy of Osteopathy Affiliated with the International Alliance of Healthcare Educators Member of the International Society of Lymphology Director of Lymph Drainage Therapy seminars Scottsdale, Arizona MISHA RUTH COHEN, OMD, LAc Clinic Director, Chicken Soup Chinese Medicine Research and Education Chair, Quan Yin Healing Arts Center Faculty, Institute for Health and Aging University of California, San Francisco San Francisco, California

JAMES A. DUKE, PhD Retired Economic Botanist USDA Senior Science Advisor Nature's Herbs Fulton, Maryland SUNDAY T. EKE-OKORO, Dr Med Sc Research Fellow Physical Medicine and Rehabilitation University of Medicine and Dentistry of New Jersey Stratford, New Jersey TIFFANY FIELD, PhD Director, Touch Research Institutes Pediatrics Department University of Miami School of Medicine Miami, Florida MARY LOU GALANTINO, PT, MS, PhD Professor of Physical Therapy Richard Stockton College of New Jersey Pomona, New Jersey Clinical Specialist University of Pennsylvania Philadelphia, Pennsylvania JON D. KAISER, MD HIV Specialist, President, and Medical Director Integrative Health Consulting, Inc Faculty, Department of Medicine University of California, San Francisco Medical School Mill Valley, California JEONGMIN LEE, PhD Arizona Prevention Center University ofArizona Tucson, Arizona

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Contributors

RYAN HEATH LESS, MS (Oriental Medicine), LAc, DiplAc, DiplCH StaffAcupuncturist, Healing Arts Department Kripalu Center Lenox, Massachusetts Director, New England Acupuncture and Herb Clinic Pittsfield, Massachusetts XINFANG MA, MD, MPH Laboratory Director Illinois Department of Public Health Springfield, Illinois STEPHEN J. MERRILL, PhD Professor of Mathematics Department of Mathematics, Statistics, and Computer Science Marquette University Milwaukee, Wisconsin ROBERT S. ROOT-BERNSTEIN, PhD Professor of Physiology Physiology Department Michigan State University East Lansing, Michigan JOHN F. RUHLAND, ND Naturopathic Medicine Faculty Bastyr University Seattle, Washington ARTHUR D. SHATTUCK, LAc NCCAOM Physician of Oriental Medicine Clinical Director Wisconsin Institute of Chinese Herbology Racine, Wisconsin

ELLEN SMIT, PhD, RD Assistant Professor Department of Social and Preventive Medicine University at Buffalo, The State University of New York School of Medicine and Biomedical Sciences Buffalo, New York LEANNA]. STANDISH, ND, PhD, LAc Director of Research Bastyr University Research Institute Bastyr University Seattle, Washington ALICE M. TANG, PhD Assistant Professor Department of Family Medicine and Community Health Tufts University School of Medicine Boston, Massachusetts JOHN E. UPLEDGER, DO, OMM, CST-D President and Medical Director The Upledger Institute, Inc. Palm Beach Gardens, Florida RONALD ROSS WATSON, PhD Professor of Public Health, Family and Community Medicine, and Nutritional Sciences Health Promotion Sciences College of Public Health University ofArizona Tucson, Arizona KOZO YOSHIKAWA, MD Arizona Prevention Center University ofArizona Tucson, Arizona

This book is dedicated to AIDS doctors all over the world. LJS

To AIDS-affected patients, whose daily spirit and ingenuity have provided uncountable scientific and moral lessons for us.

ee This book is dedicated to my two children, Madison and Daniel, both ofwhom were conceived and born during theyears ofthis book project. MLG

Series Introduction

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he aim ofthis Series is to provide clear and rational guides for health care professionals and students so they have current knowledge about: • Therapeutic medical systems currently labeled as complementary medicine • Complementary approaches to specific medical conditions • Integration of complementary therapy into mainstream medical practice Each text is written specifically with the needs and questions of a health care audience in mind. Where possible, basic applications in clinical practice are explored. Complementary medicine is being rapidly integrated into mainstream health care largely in response to consumer demand but also in recognition of new scientific findings that are expanding our view of health and healing-pushing against the limits of the current biomedical paradigm. Health care professionals need to know what their patients are doing and what they believe about complementary and alternative medicine. In addition, a basic working knowledge of complementary medical therapies is a rapidly growing requirement for primary care, some medical specialties, and the allied health professions. These approaches also expand our view of the art and science of medicine and make important contributions to the intellectual formation of students in health professions. This Series provides a survey of the fundamentals and foundations of complementary medical systems

currently available and practiced in North America and Europe. Each topic is presented in ways that are understandable and that provide an important understanding of the intellectual foundations of each system-with translation between the complementary and conventional medical systems whenever possible. These explanations draw appropriately on the social and scientific foundations of each system of care. Rapidly growing contemporary research results are included whenever possible. In addition to providing evidence indicating when complementary medicines may be of therapeutic benefit, guidance is also provided about when complementary therapies should not be used. This field of health is rapidly moving from being considered alternative (implying exclusive use of one medical system or another) to complementary (used as an adjunct to mainstream medical care) to integrative medicine (implying an active, conscious effort by mainstream medicine to incorporate alternatives on the basis of rational, clinical, and scientific information and judgment). Likewise, health care professionals and students must move rapidly to learn the fundamentals of com· plementary medical systems to better serve their patients' needs, protect the public health, and expand their scientific horizons and understanding of health and healing. MARC S. MICOZZI

Philadelphia) Pennsylvania 1997

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Series Editor's Preface

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he book series, Medical Guides to Complementary & Alternative Medicine, is designed to provide the health professions with authoritative, credible information about therapeutic modalities and healing systems collectively known as complementary and alternative medicine (CAM). Existing titles in the series are organized by therapeutic system (e.g., Ayurveda, medical hypnosis, osteopathic medicine, chiropractic, acupuncture), following the organization of my basic text, Fundamentals of Complementary and Alternative Medicine, second edition, 2001, and by medical specialty practice (e.g., neurology, rehabilitation medicine). This title introduces a third category of text providing CAM approaches by medical condition. Together with the forthcoming title on alternatives in cancer, AIDS and Complementary & Alternative Medicine is the first to address the subject in this way. The editorial team consists of the leaders of the first NIH-funded grant to study the full scope of CAM approaches to AIDS, awarded to Bastyr University in Seattle, together with my colleague in the Department of Rehabilitation Medicine at the University of Pennsylvania. They provide the first systematic and credible review of this topic based on their experience with the NIH-sponsored epidemiological investigations, as well as their own clinical experiences. People with AIDS represent a well-organized, vocal, and highly motivated group in the area of public health and public policy. Likewise, this volume provides a unique and useful resource as they continue to actively pursue therapeutic options and question medical scientific orthodoxy. One important question expresses doubt about the pathogenesis of AIDS. Although the "politically correct" decision

was made by funding agencies several years ago to equate the clinical entity AIDS with the causative agent HIV, others, including a recent Nobel laureate, question the primary role of the virus. This volume addresses both those questions and concerns that highly toxic antiviral treatment for HIV infection may actually contribute to the pathogenesis of AIDS. The global AIDS pandemic is testimony to the limits of the twentieth-century approach to control of infectious diseases. The nineteenth-century germ theory of disease led to great advancements in the treatment of bacterial infections with antibiotic "magic bullets." The eventual development ofbacterial drug resistance turned magic bullets into "friendly fire." This problem of bacterial infections and the relative difficulty and expense of treating viral infections with drugs requires us to reexamine some ofour century-old assumptions about the causes and control of infectious diseases. A focus on host factors and selective stimulation and modulation of the immune system may represent useful new ideas that can help account for some of the clinical variability observed in infection, as well as compensating for the growing shortcomings of our long-term war against microbes. Many herbal remedies from Asian (e.g., Chinese medicine and Ayurveda) and Native American medical traditions have been observed to help modulate the immune system. Clearly, CAM has much to contribute to the support ofAIDS patients, and people with AIDS have been quick to resort to these methods. The health professions, as well as people with AIDS, have compelling reasons, rights, and needs to learn more about what CAM therapies have to offer in the treatment of AIDS-both to provide better and Xl

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Series Editor's Preface

more affordable care to United States citizens and to expand our view of health and healing in American medicine. Because the rest of the world cannot afford conventional AIDS treatment, our renewed study of CAM may provide an opportunity to return a little of

the wealth of medical knowledge we are obtaining from the health traditions of other cultures around the world. MARC S. MICOZZI Philadelphia, Pennsylvania 2001

t's funny how things always seem to turn out for the best. In September 1998 this book was written and mailed to a publisher. The previous two years, 1996 to 1998, were a time when all of us involved in HIV research and clinical care were more and more certain that combination highly active antiretroviral therapy (HAART) was truly helping people with AIDS. Unforeseen developments resulted in our manuscript being assigned to new editors in 2000. They asked Dr. Calabrese, Dr. Galantino, and me if we were still interested in publishing this book. Somewhat reluctantly, we said yes. Our editors explained that we would need to update the book. After all, two critical years of AIDS science and medicine had elapsed. Updating the book was a daunting task, but we accepted, and the result is the appearance of this book 3 years after the original manuscript was written in 1998. We are glad now that we were forced to look at the book and the field with fresh eyes. At the turn of the twenty-first century many wonderful and ominous things were happening in AIDS medicine and especially in combination HAART. We were asked to update our book at a time when it was obvious that conventional medicine, and the entire military industrial complex ofwhich it is a part, had invented, developed, and tested the first truly important therapy for HIV infection and AIDS. This was a staggering achievement. Any doctor who has worked in the AIDS field has seen men and women dying of AIDS slowly get well enough to venture back into life from their homes, beds, and wheelchairs, return to graduate school or work, family, and a love life. Before the development ofHAART, we had seen hundreds of people die despite our best efforts, but things in the West are different now. Some of our patients tell us confiden-

9

tially that they now have the damnable luxury of healthy persons: to suffer either ontological despair or the pain and beauty of a new love. When we were finished with the first version of the book in 1998, it seemed that alternative medicine had failed in its mission to cure AIDS. We can remember feeling dispirited about the whole book project after the final draft was written and even worse when contemplating the revised update. After all, what was there to say at this point? That we were wrong about HIV not causing AIDS? That we were disappointed that we and the entire complementary and alternative medicine (CAM) community had produced such a disappointingly small, tattered array of controlled clinical studies? That we were disappointed in the paucity of research data despite approximately 70% of HIV-positive men and women across the United States using CAM to treat their HIV disease? How uninspiring to say in a book that none of the exciting, experimental CAM therapies that had so many supporters in urban politicized gay male culture have not panned out as dramatically useful therapies. Too many exciting CAM therapies, when examined closely, seemed to dissolve into nothing. However, this was also a time when the side effects of HAART were discovered, and there was global consternation that over 97% of the world's HIV-infected persons had no access to HAART. Today's research and medical challenges of HIV/ AIDS in the urban West are to develop HAART regimens that have fewer side effects and that better manage those side effects of HAART, which include diabetes, lipodystrophies, peripheral neuropathies, and hyperlipidemias. Thankfully, our editors, Kellie Conklin and Jennifer Watrous, asked us to look at CAM in HIV/ AIDS again and to do another complete search of the peerXU1

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Preface

reviewed biomedical literature. This rewriring process led us to a deeper understanding. We have a more mature perception of the role ofCAM in the emerging integrative medicine movement that was in part inspired by the AIDS epidemic and the effective radical political organizing that occurred in minority communities across the United States. Exciting basic science developments have been promoted by CAM AIDS research (for example, see Chapter 9). HIV/AIDS is an excellent research model for basic and clinical research, because it has reasonably correlated clinical and biological markers. Because of the unquestionable success ofHAART, there is renewed justification for studying the anti-HIV effects of a combination of botanical and antiretroviral activity. Because ofCAM research over the last decade, we now have preliminary evidence that certain nutritional, behavioral, botanical, and homeopathic approaches, as well as acupuncture, are effective in the treatment of several HIV-related conditions. We realized that the role has changed for alternative medicine, now more comfortably called complementary medicine. The role in HIV/ AIDS is truly that of complementarity, and it is on this goal that CAM research should focus. What do we know thus far? It is safe to suggest that we know the following from the past 15 years of CAM clinical research: 1. Suppression of HIV by a combination ofantiretroviral drugs improves clinical and laboratory signs and symptoms ofHIV infection and AIDS. 2. Those brave, although some thought foolish, CAM providers who advised their patients to delay use of AZT for as long as possible were correct. Many of those patients infected with HIV in the 1980s who eschewed AZT are alive today to benefit from the HAART regimens. Ironically, many of these regi-

mens include the very AZT that was once so scorned. 3. There may be an important role for certain CAM therapies in managing some of the disease processes involved in HIV infection and in treating some of the adverse effects ofHAART and prophylactic antibiotics. We wish to thank the brilliant, committed men and women of the NIH, CDC, FDA, and the virological pharmaceutical companies for their staggering achievement in the development of HAART. We do not know what the total cost of this lO-year effort was between 1986 and 1996. We wonder what CAM researchers could claim as achievements today ifsimilar resources and focus were put into CAM research in HIV/ AIDS. We understand that the absence of financial incentives for natural products decreases entrepreneurial research, which is why the work of the NIH National Center of Alternative and Complementary Medicine (NCCAM) and its predecessor, the NIH Office of Alternative Medicine (OAM) is so important. The public needs to know about the safety and efficacy of CAM botanical, nutritional, and biological treatments. It will be up to the federal government to fund and direct this work at a national level. We hope that this book will reinvigorate CAM research in HIV/AIDS. As we point out in this book, some promising avenues of basic and clinical research exist, but there still is much to do. Funding for research is now in place at the NIH. People with AIDS still need us. Let us proceed with vigor into the next decade of CAM research on HIV and AIDS. LEANNA J. STANDISH CARLO CALABRESE MARY LOU GALANTINO

Acknowledgments

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e warmly thank Heather Bradley for managing and coordinating this large and detailed project for 2 years. This book would never have happened without her competent and thorough dedication. We also wish to thank the members of the scientific and technical staff of the Bastyr University AIDS Research Center. We are grateful to Cherie ReevesSperr, the Center's Project Manager, for 3 years ofdedicated work that led to the most complete set of data regarding alternative medicine use among HN-positive men and women in the United States. We also wish to thank Jose Berger, MF, Matt Brignall, NO, Jung Kim, and Langley Douglass for their expert literature and reference review work. This project was made easier and more lighthearted by the constant support ofTove Hansen and Michele Bivins, our Administrative Assistants, and Maura Murphy, our Office Manager, who reminded us that we cold do this book and that it was worth doing. We give grateful thanks to the brave men and women of the National Institutes of Health (NIH) Office of Alternative Medicine (DAM), who believed in the then-controversial concept that alternative medicine required investigation and supported Bastyr University's HIV/AIDS research with a grant: between 1994 and 1998. This study was supported by the NIH Office of Complementary and Alternative Medicine (OCAM), the National Institute of Allergy and Infectious Diseases (NIAID), and the NIH Office of Research on Women's Health (ORWH). We especially want to acknowledge the hard-nosed dedication of the staff at the NIH DAM (now the National Center for Complementary and Alternative Medicine [NCCAM]). Our special thanks go ro

Richard Nahin, PhD; Steven Groft, PhD; Wayne Jonas, MD;John Spencer, PhD; and Victoria Carper, MPA. LJS Deep thanks ro Joe Pizzorno, ND, and the Board of Bastyr University, who provided the home where the groundwork was done; to my partners at the Bastyr University Research Institute, who were a fascinating and inspiring family; and to my co-editors, who made this book a wonderful experience. When you're headed in the right direction, all you need to do is keep going. CC "It is better to light one small candle than to curse the darkness"-Chinese Proverb Many candles have been lighted throughout the HIV epidemic; many hopes and dreams for advances in various domains of integrative therapies. Those living with HN disease ignited the way for my personal and professional exploration of complementary therapies, and I thank each person who presented their srory and experience with me since the early 1980s. As this book evolved, I am grateful for the support of Marc Micozzi, MD, PhD, who envisioned this text in the series of complementary and alternative medicine books. I appreciate the dedication of my co-editors, Leanna Standish and Carlo Calabrese, for our discussions about the vision for this book and their continued commitment to research in complementary therapies. Technical support is the most crucial aspect in the logistics ofsuch an endeavor, and I especially want ro thank Heather Bradley, Carleen Finkle, GwenJones, and Amy Taylor-for without them, the organization and computer dynamics for the substrate of the book would not be forthcoming. Finally, I am grateful to my husband, David Pack, who knows my passion for this work and supports me unconditionally through it all. MLG

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AIDS and CAM How We Got Here LEANNA CARLO MARY

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he

J.

STANDISH

CALABRESE LOU

GALANTINO

conventional and alternative medical communities responded to the AIDS epidemic in different ways. Conventional biomedical scientists and practitioners, as well as alternative medicine theorists and practitioners, sought and sometimes claimed medical solutions to human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The conventional biomedical community, including federal agencies, major universities, and the pharmaceutical industry, contributed enormous effort and money toward developing a synthetic drug or combination of drugs that would selectively destroy HIV in the infected host. The alternative medicine community responded to AIDS differently. Some parts of the alternative medical community distrusted the pharmaceutical indus-

try, and some even questioned the theory that HIV causes AIDS. What was most significant for the development of the field ofHIV/ AIDS complementary and alternative medicine (CAM) was that practitioners were faced with HIV-positive and AIDS patients who were often desperately seeking help. Some patients came to CAM practitioners looking for miracle cures, while some sought help for HIV-related symptoms. Others sought alternative medicine to escape from the "HIV = AIDS = death" school of thought that seemed endemic in conventional medical settings in the early years of the epidemic. Some patients came to CAM practitioners looking for hope and camaraderie. As a result, many alternative practitioners felt called on to apply their modalities to HIV-infected patients. From the beginning of the American AIDS epidemic, more than a few alternative therapies claimed to "cure"

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AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

AIDS. Advocates from the HIV-infected community, health-care providers, and drug manufacturers claimed at times that certain botanicals, oxygenation therapies, Chinese herbal medicines, homeopathy, and bioelectromagnetic therapies could eradicate the virus, restore immune function, or both. The CAM movement in the United States gained momentum over the last decade through its mobilization around the AIDS issue and in response to the needs of people living with HIV. Urban gay communities began organizing politically and socially around AIDS in the mid-1980s. Some CAM advocates and providers were part of both the interrelated American AIDS and gay sociopolitical movement in the major coastal cities of the United States. Strong advocates, often patients themselves, or politicized gay males spoke out in the AIDS or gay community media in favor of research in alternative medicine and in alternative therapies in particular. Great achievements were made in the science of AIDS etiology and pathogenesis. A series ofantiretroviral drugs were developed that lower viral counts to undetectable levels in peripheral blood samples using current technology of polymerase chain reaction (PCR) and branched-chain DNA amplification. Dramatic changes occurred in the health status of many HIV/AIDS patients starting in March 1996, when triple antiretroviral therapy (ART), including protease inhibitors (PIs), was made widely available to those HIV-infected patients who had a knowledgeable physician, medical insurance, or disposable income that could be spent on this therapy, which costs between $1000 to $2000 per month. At the June 1996 International AIDS Conference in Vancouver, British Columbia, international AIDS experts and members of the HIV-affected communities from allover the world admonished the medical community because combination ART although effective in suppressing HIV activity, was available only to 3% of patients worldwide who were infected with HIV. The remaining 97% of HIVinfected people live in countries where ART is typically inaccessible. Combination ART was the first significant breakthrough in controlling the virus that presumably initiates the cascade of events that leads to deterioration of the immune system. Zidovudine (AZT) was the first antiretroviral drug approved by the Federal Drug Administration (FDA) in 1987 for the treatment of HIV. This was the beginning ofthe development of"highly active" ART (HAART). These useful antiviral (AV) drugs are not

without their toxicities. AZT was the first nucleoside analog antiretroviral drug approved for use by the FDA. For many, AZT was without long-term clinical benefit. Some critics suggested that AZT made many HIVpositive patients worse and may even have hastened their demise. While this remains controversial, AZT is known to cause anemia, peripheral neuropathy (PN), and gastrointestinal (GI) complications in many patients. It appears that the global HIV epidemic is accelerating. Disturbing epidemiological findings presented at the annual International AIDS Conferences suggest that the rate of HIV infection in Africa continues unabated. Currently, 90% of all HIV-infected people live in developing countries where combination ART is unavailable. It is estimated that between 30% to 40% of pregnant women in Harare, Zimbabwe, in subSaharan Africa are infected with HIV. It has been reported that 27% of Ugandan military personnel are infected with HIV. HIV infection rates increased in Russia by nearly 49-fold between 1991 and 1997. The AIDS epidemic is not over and the need to evaluate alternative treatments for HIV/ AIDS is undiminished. It is important to know if the claims that have been made for ozone, dinitrochlorobenzene (DNCB), Kemron, dehydroepiandrosterone DHEA, high-dose antioxidant vitamins, or electromagnetic (EM) therapies are valid. Despite the widespread use of CAM therapies by and for HIV/ AIDS patients, very few of these therapies have been evaluated in randomized, controlled clinical trials (RCTs). Nevertheless, the number of alternative therapies used by HIV-positive Americans is astonishing. Currently the most comprehensive description of alternative medicine use among HIV-positive Americans comes from the Bastyr University's Alternative Medicine Care Outcomes in AIDS (AMCOA) study. This nationwide observational study enrolled 1666 HIV-positive men and women between 1995 and 1997 who were self-identified users of alternative medicine for HIV/ AIDS. Alternative medicine use was categorized into different types ofproviders, substances, and treatment activities garnered from the scientific literature, newsletters, clinicians, and buyers clubs. The cohort reported the use of a total of 1492 alternative treatments for HIV, many ofwhich were administered or prescribed by 119 distinct CAM provider types. Very few of these alternative therapies have been subjected to clinical evaluation. A systematic search of MEDLINE and AIDSLINE was performed by the

AIDS and CAM

Bastyr University AIDS Research Center to locate RCTs published in peer-reviewed journals on CAM. Table 1-1 presents a current summary of published RCTs for HIV/ AIDS CAM therapies in use. Although 1492 alternative therapies are currently used by HIVpositive patients as of the year 2000, only 45 RCTs

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have been published, which evaluate only 24 of these therapies. The need for research is great indeed. Over the last decade some of the philosophy and technology of alternative medicine has slowly been mainstreamed, and now many scientists, physicians, insurance companies, hospitals, and HMOs are

TABLE 1-1

Randomized Clinical Trials (45) in HIV/AIDS Complementary and Alternative Medicine This table represents all ofthe Refs on CAM therapies for HIV published before 2001 in peer-reviewed journals, and although not journals published in the United States, they must have an English abstract. The table was compiled from MEDLINE and AIDSLINE searches, with the criteria for inclusion being that the studies be controlled and randomized. In some cases the studies were also placebo controlled. * Treatment

Author

Number ofsubjects

Findings

Acemannan (Aloe)

Weerts (1990)

47 HIV+ patients

Montaner (1996)

63 HIV+ males

Acupuncture

Shlay(1998)

239 HIV+ subjects

Aerobic exercise

La Perriere (1990)

50 asymptomatic gay males

Rigsby (1992)

37 HIV-1 + patients

Stringer (1998)

34 HIV+ patients

Perna (1999)

28 HIV+ subjects

Spence (1990)

24 HIV+ males with PCP

250 mg po qid for 24 weeks was not effective in reducing the hemotoxicity ofAZT. 400 mg po qid in patients taking AZT or ddt did not prevent CD4 decline or have significant effect on quantitative virology. 14 weeks standardized acupuncture regimen was not effective in treating pain due to HIV-related PN. 5 weeks aerobic training, before notification of HIV-positive status, led to attenuation of detrimental immunological response associated with notification of HIV-positive status. 12-week regimen, including aerobic and strength training, was associated with increased strength and cardiopulmonary function but not with changes in immune status. 6 weeks moderate or heavy training led to increased fitness and QOL measures but did not significantly affect immune function. 12 weeks laboratory-based aerobic exercise program led to an increase in CD4 cell counts as long as the individuals adhered to the exercise regimen. 6 weeks resistance exercise training led to an increase in 13 of 15 anthropometric measures.

Anaerobic exercise

pcp, Pneumocystis carinii pneumonia; ESR, erythrocyte sedimentation rate; CRp, C-reactive protein; IL-6, interleukin-6; PN, peripheral neuropathy; QOL, quality oflife; SGA, small for gestational age; TMP-SMX, trimethoprim-sulfamethoxazole. Continued *See Table 1-1 references at the end of this chapter.

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AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

TABLE 1-1

Randomized Clinical Trials (45) in HIV/AIDS Complementary and Alternative Medicine-contJd Treatment

Author

Number of subjects

Findings

Arginine/Omega 3 fatty acids

Pichard (1998)

64 HIV+ patients with CD4 >100/mm 3

Beta-carotene

Coodley (1996)

72 HIV+ patients

Coodley (1993)

21 HIV+ patients

Sankary (1989)

18 asymptomatic HIV+ males

Burack (1996)

30 HIV+, non-AIDS, CD40f200499/mm 3

Weber (1999)

68 HIV+ adults

DHEA

Evans (1997)

16 HIV-l +

Ditiocarb sodium

Reisinger (1990)

60 HIV+ patients

Lang (1988)

83 HIV+ patients

HIV87 study group (1993)

1333 HIV+ patients

Falguera (1995)

75 HIV+ patients with CD4<500/mm 3 being treated with ART 45 ARC patients

7.4 g arginine given with 1.7 g omega-3 fatty acid for 6 months did not lead to change in viral or immune measures. Both groups also received daily nutritional supplement. 60 mg tid for 3 months did not lead to significant change in several measures of immune function. Both treatment and placebo groups received multivitamin supplement. 180 mg qd for 4 weeks led to significant increase in WBC count, % change in CD4, and % change in CD4:CD8 ratio. Absolute CD4 cell count elevated but not significantly. 50 mg Anginlyc tid had significant positive effect on CD4 cells and anti-p24 antibodies. 28 tablets of a mixture containing 31 Chinese herbs showed insignificant improvement in QOL and decrease in symptoms. 4 daily doses of a standardized preparation of35 Chinese herbs did not improve QOL, clinical manifestations, plasma virus loads, or CD4 cell counts. 50 mg bid had no significant effect on ESR, CRP, or IL-6. 24 weeks IV treatment significantly delayed disease progression. Benefits of oral treatment were not significant. 16 weeks treatment significantly increased immune function and clinical status, while decreasing constitutional symptoms. Risk of progression to AIDS was significantly higher in ditiocarb group than placebo group. 15 mg qd folic acid, with monthly 1000 Ilg 1M doses ofB'2' did not reduce the risk of myelosuppression associated with AZT. 6 months treatment led to significantly reduced number of AIDS-defining events.

Chinese herbs

Folate/Vitamin

B12 IMREG-l

Fiala (1991)

PCp, Pneumocystis carinii pneumonia; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; IL-6, interleukin-6; PN, peripheral neuropathy; QOL, quality of life; SGA, small for gestational age; TMP-SMX, trimethoprim-sulfamethoxazole.

5

AIDS and CAM

TABLE I-I

Randomized Clinical Trials (45) in HIV/AIDS Complementary and Alternative Medicine-cont'd Treatment

Author

Number of subjects

Findings

IMREG-1-cont'd

Gottlieb (1991 )

143 ARC patients

L-carnitine

DeSimone (1994)

20 HIV+ patients

Massage therapy

Birk (1996)

42 HIV+ patients

Scafidi (1996)

28 neonates ofHIV+ mothers

Fawzi (1998)

1075 HIV+ Tanzanian women 12-27 weeks gestation

Fawzi (2000)

1083 HIV+ pregnant women

Akerlund (1997)

15 HIV+ patients with CD4<200/mm 3

Walmsley (1998)

238 HIV+ patients on TMP-SMX treatment 69 HIV+ patients, 40 with ART, 29 without ART

Experimental group experienced fewer constitutional symptoms and slowed CD4 decline during 6 month trial. 6 g/day for 4 months produced significant increases in CD4 counts and less substantial increases in CD8 counts. 12 weeks massage therapy, with or without exercise training or stress management training, had no significant effect on immune function or QOL. 15 minutes massage therapy tid for 10 days was associated with increased weight gain and Brazelton performance scores. Supplementation reduced risk of low birthweight, prematurity, SGA infants, and fetal death, as well as increasing counts ofCD4, CDS, and CD3 cells. Vitamin A and multivitamin supplementation showed no effect on vertical transmission of HIV in utero or intrapartum and had no effect on birth weight of infants born HIV+. 800 mg qd did not significantly decrease risk of adverse reactions to pharmacological prophylaxis against PCP. 3 g/day did not show significant effect on TMP-SMX hypersensitivity. 7 month double-blind placebo trial indicated that immunological function impairment may result from cysteine deficiency. 8 weeks ozone therapy did not significantly affect immune parameters or p24 antigen. 12 weeks intranasal administration led to no change in symptoms of neuropathy or CD4 count. 6 mg/day did not product significant improvement in cognitive function. 600 mg tid of NAC given with 500 IJg qd selenium, was associated with increase in CD4% but no change in glutathione levels or viral load.

Multivitamins

N-Acetylcysteine

Breitkreutz (2000)

Ozone

Garber (1991)

PeptideT

Simpson (1996)

Selenium/NAcetylcysteine

14 HIV+ subjects with CD4 counts 200400/mm 3 81 HIV+ patients with DSP

Heseltine (1998)

Trial size not indicated

Look (1998)

24 antiretroviral naIve HIV+ outpatients

Continued

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AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

TABLE 1-1

Randomized Clinical Trials (45) in HIV/AIDS Complementary and Alternative Medicine-cont'd Treatment

Author

Number of subjects

Findings

Stress management

Coates (1989)

64 HIV+ gay males

Taylor (1995)

Cruess (1999)

10 HIV+ asymptomatic males with CD4 <400/mm 3 43 HIV+ males

Antoni (2000)

73 HIV+ males

Support group

Goodkin (1998)

74 HIV+ and 45 HIVgay males

Thymopentin

Conant (1992)

91 asymptomatic HIV+ patients

Vitamin A

Kennedy (2000)

312 HIV+ pregnant females

Humphrey (1999)

40 HIV+ females of reproductive age

Semba (1998)

120 HIV+ IV drug users

Coutsoudis (1995)

118 children ofHIV+ mothers in South Africa

Vitamin B12

Navarette (1989)

49 subjects treated withAZT

Zinc

Ancarani (1993)

25 asymptomatic HIV+, CD4 <500/ml

8 2-hr sessions and 1 all-day retreat led to significantly fewer sex partners in month of treatment but no change in lymphocyte numbers. 20 biweekly sessions led to improved mood, self-esteem, and T-cell counts through 1 month follow-up. 10 weekly sessions of cognitive-behavioral stress management intervention can buffer against decrease in DHEAS. 12 months of cognitive-behavioral stress management intervention produced significant increases in CD4 and COB cell counts, as well as improvement in self-reported anger, anxiety, and mood swings. 10 weekly sessions were associated with significant increase in CD4 count, total T lymphocytes, cortisol levels, medication usage, and disease progression. 50 mg SQ three times/week for 24 or 52 weeks led to insignificant reduction in disease progression. 5,000 IU/day with 30 mg beta-carotene and treatment of200,000 IU at delivery did not produce significant decrease in HIV symptoms either prenatal or postnatal. Single dose of300,000 IU did not present significant clinical or immunological adverse effects. Single dose of200,000 IU had no effect on CD4 count or viral load at 2 and 4 weeks. Vitamin A (50,000-200,000 IU) given every 3 months reduced hospital admissions for diarrhea 77% and lowered overall morbidity in HIV+ infants. 1000 IJg given weekly 1M had no significant effect on MCV or Hb levels. Both groups received 50 mg folinic acid weekly 1M. 200 mg zinc sulfate qd for 1 month significantly improved thymulin concentration, as well as CD4 and CD8 cells. Effects reversed within 2 months of treatment cessation.

PCp, Pneumocystis carinii pneumonia; ESR, erythrocyte sedimentation rate; eRP, C-reactive protein; IL-6, interleukin-6; PN, peripheral neuropathy; QOL, quality of life; SGA, small for gestational age; TMP-SMX, trimethoprim-sulfamethoxazole.

AIDS and CAM

content with the inclusion ofalternative medicine. Alternative medicine is now given the more benign and less controversial name of complementary and alternative medicine, and its acronym CAM is in common use. Alternative meant "instead of," or worse, "opposed to." Complementary means "to complete," implying at its best a cooperative co-management parallel to the biomedical mainstream, or at least a potential source of clinical ideas and theories. Some members of the CAM community suggest that while CAM never succeeded in curing anyone of AIDS, the nontoxic physiological, psychoemotional, and spiritual support provided by CAM therapists helps people live longer, perhaps long enough to benefit from recently developed HAART. The AIDS epidemic had a significant effect on the history of science and medicine. The AIDS crisis generated, by the need for effective action, some of the clearest thinking among scientists and clinicians, and it forced the creation of new scientific vistas. Our understanding of the immune system was considerably advanced by insights provided from the study ofAIDS patients and their cell systems. We now know much more about the immune system and the mechanisms that underlie both immune deficiencies and autoimmunity than we did fifteen years ago. We also know much more about nutrition, immunity, and psychoneuroimmunology (PNI), as well as the antibiotic treatment (and its limitations) of parasitic and bacterial infections. The AIDS epidemic also changed the alternative medical community. Practitioners of Chinese and naturopathic medicine, as well as chiropractors, nutritionists, massage therapists, herbalists, homeopaths, and many others, responded to the needs of the HIVpositive community. For example, in the early days of the American AIDS epidemic, acupuncturists in San Francisco and New York were either called on or took it on themselves to help people with AIDS. There is now preliminary evidence that acupuncture may be an effective therapy for PN, a common manifestation of the disease (see Chapter 11). In November 1997 the National Institutes of Health (NIH) published a Consensus Development Statement to provide health care providers, patients, and the general public with a responsible assessment of the use and effectiveness ofacupuncture. Acupuncture is widely practiced in the United States as a therapeutic intervention. Whereas there are many studies of acupuncture's potential usefulness, many of these

7

studies are of marginal design and provide equivocal results. The issue is complicated further by inherent difficulties in finding appropriate experiment controls, such as placebos or truly ineffective sham acupuncture treatment (see Chapter 1). Promising results emerged, for example, demonstrating the efficacy of acupuncture in nausea and vomiting that can occur in adults postoperatively and with chemotherapy. In conditions as diverse as addiction, stroke rehabilitation, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low back pain, carpal tunnel syndrome, and asthma, acupuncture is useful as an adjunct treatment in a comprehensive treatment program or even as an acceptable alternative. Further research is likely to expand evidence for the therapeutic potential ofacupuncture. CAM practitioners were asked by their patients to help handle some of the complex effects of the myriad of drugs they were prescribed, many of which have known toxicities. Many practitioners agree that combining CAM with good conventional medical care is the ideal. Evidence presented in Chapter 24 reflects this ideal. The CAM community did not jump to any premature conclusions about the pathophysiology or effective treatment principles for HIV infection and AIDS. Future medical historians will write about the rapid scientific consensus that formed about the cause of"gayrelated immune deficiency" (GRID) after Robert Gallo's announcement in 1984 of the discovery ofHIV that preferentially affected T lymphocytes and caused AIDS. There is evidence that HIV is neither necessary nor sufficient in the etiology ofAIDS, although most scientists agree that HIV is very closely associated with it. Alternative theories of the origin and pathogenesis ofAIDS helped shape many of the CAM therapies that are still used today. For example, the hypothesis that HIV infection occurs with other viruses, the socalled cofactor viruses, such as herpes simplex virus (HSV), hepatitis, human papillomavirus (HPV), and Epstein-Barr virus (EBV) (see Chapter 2), lead naturopathic physicians to emphasize early treatment to control or clear cofactor viruses. Despite the current popularity ofalternative medicine in industrialized nations, alternative medicine has not had an easy time. The entire field of CAM has many critics. The main and most valid criticism is that CAM treatments frequently lack supporting scientific evidence. However, a surprising amount of evidence exists for many of the commonly used HIV CAM

8

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

therapies, such as antioxidants, multiple vitamins, acupuncture, massage, and others. The purpose of this book is to present some of that evidence. In light of the successes ofHAART, is there need for research, let alone a book, on alternative medicine in HIV/AIDS? Nevertheless, evidence shows that although combination ART is often effective in reducing viral replication, ART does not restore immune function. Many sessions of the International AIDS Conference held in Durban, South Africa, in June 2000 focused on immune restoration strategies, but only the bare beginnings of clinical approaches exist. As we show in this book, a rational scientific basis exists for many of the complementary and alternative methods used to treat HN/ AIDS. For example, there is good evidence that vitamin and mineral therapies have positive effects on immune function and disease progression (see Chapters 4 and 5). Evidence also shows that several herbs have significant antiretroviral effects (see Chapter 6). One of the tasks of CAM is to develop a natural antiretroviral combination that interferes with HN replication at multiple points in its life cycle. Preliminary evidence shows that homeopathically prepared substances have immunological and virological activity in vivo (see Chapter 9). Acupuncture techniques are shown to be clinically effective in several HN-related complications (see Chapters 11 and 21). In 1992 the NIH established the Office ofAlternative Medicine (OAM) to study alternative medicine. The Congressional mandate for the OAM was to "screen and evaluate promising therapies from unconventional medical practices." The OAM established ten research centers in the United States to study alternative medicine in 1994 to 1997, including the Bastyr Center, through a 3-year cooperative agreement grant with the OAM and administered through the National Institute of Allergy and Infectious Disease Office of AIDS. Whereas scientific and political controversy surrounds the issue of alternative medicine and its application in HN and AIDS, justification exists for federally funded research in this area. The justification for greater support for HN/ AIDS alternative medicine research falls within the following five areas: 1. The use ofalternative medicine in the HN-infected community is widespread, and yet the medical and scientific community knows little about either the safety or efficacy of most of these treatments. The media and the health products industry advertise

sometimes intriguing or outrageous claims of efficacy for a variety ofagents, modalities, and devicesclaims that are largely unexamined. 2. Some of the more extreme therapies prescribed by CAM providers and self-prescribed by patients are potentially harmful. Moreover, little is known about the interaction ofalternative medicines and conventional antiretroviral drugs and antibiotics. Studies recently found that Hypericum perforatum, an herb with purported AV effects popular in the HIV community, interacts with indinavir, one of the PIs, by more rapidly reducing the drug's concentration in the body, reducing its effectiveness (see references 152 and 153 in Chapter 20). 3. Currently there is no definitive treatment for the underlying immunological disorder that leads to clinical AIDS. Moreover, treatment for several of the AIDS-defining opportunistic infections (01s) and neoplasms is as yet ineffective. Thus innovative strategies for the treatment of AIDS must be explored. 4. AIDS activist groups throughout the country continue to demand research in alternative approaches and alternative therapies. 5. Some evidence exists that a subset of alternative treatments may be effective and beneficial. For these reasons the Bastyr University AIDS Research Center in Seattle opened in October 1994. Bastyr University specializes in clinical training in natural medicine. The Bastyr University AIDS Research Center screens and evaluates hundreds ofCAM therapies, using an observational research design and studying a nationwide cohort ofHN-positive men and women who use CAM therapies. Because there is no cure, justification exists for a continued effort by the CAM community to develop and test innovative therapies for HIV/ AIDS. Some CAM practitioners have hypothesized that CAM has the potential to develop effective AV and immunoregulatory therapies that may have lower toxicity and more long-term benefits than currently available conventional therapies. Scientific progress requires diversity of thought. The alternative medicine community, including its most fringe aspects-perhaps because of its outliers-may hold new ideas about the genesis of both disease and health. Some ofwhat we have learned has been applied to other serious health problems, particularly cancer. Although antiretroviral pharmacological care of HN-infected patients has advanced significantly in the

AIDS and CAM

last few years, these drugs are not without toxicities. Patients may only be able to tolerate them for a few years. Structured interruptions are being explored as a way to deal with the drug toxicities, but interruption is a compromise to viral suppression. Even without interruption, viral resistance can occur in patients despite continuous triple drug therapy. I For these reasons, failures in HAART are increasingly common. Antiretroviral drugs are unavailable to 97% of the world's HIV-infected population due to their high cost. Utilization and development of traditional medicine may be the only health care AIDS patients receive in some parts ofAfrica and Asia. More research should be conducted to evaluate and develop less costly and less toxic AV and immune therapies. It is not impossible that findings from indigenous natural medicines may contribute to solving the AIDS problem even in the West. There are effective tools of HIV disease management among alternative medical therapies. The AIDS problem is not over, and the work of the CAM scientific and medical community is not complete.

WHAT DOES CAM MEAN TO HIV/AIDS? I In this book, alternative medicine is defined as any treatment (substance or modality) used by or prescribed for HIV-positive patients that is not an FDAapproved pharmaceutical substance or device, or the use of FDA-approved substances or devices for indications and in doses not approved by the FDA for that agent or device. The NIH Office of Alternative Medicine offers a definition of CAM that revolves around professional use of a particular medical practice. A medical practice is considered highly CAM when it is not available in hospitals, not taught in medical schools, physicians are not typically trained in it, research funding is not available, the practice is not licensed in states, and insurance companies do not reimburse for it. Wayne Jonas, MD, the former Director of the NIH Office of Alternative Medicine, defines CAM as a "subset of medical and health practices that are not an integral part ofconventional (Western) medicine."2 Jonas also describes the spectrum of CAM by dividing CAM into three categories, depending on how integrated the practice is within conventional medicine. In Figure 1-1, Jonas describes three areas of CAM as integrating areas, emerging areas, and frontier areas.

9

Recently published data show that an increasing number of Americans use some form of alternative medicine. 3 ,4 This rate is higher among the HIV/ AIDS population. A number ofstudies suggest that over half ofall HIV-positive gay or bisexual men are using alternative medical therapies; one of the most common is Chinese medicine. 5 •6 Some estimates show that use of alternative medicine among HIV-positive adults is as high as 78%.7 Despite their widespread use, most of these alternative therapies have not undergone adequate clinical evaluation. Alternative therapy use in the HIV-infected community includes alternative health care providers, alternative substances, and alternative modalities. Licensed alternative providers include naturopathic physicians, chiropractors, acupuncturists, massage therapists, and hypnotherapists. Examples of commonly used alternative substances include high dose vitamins, minerals, and antioxidants administered both orally and intravenously (e.g., vitamin C, E, BI 2> niacin, zinc, selenium, beta-carotene, N-Acetylcysteine); botanical medicines (e.g., SPV-30, aloe vera, Carnivora, Glycyrrhiza glabra, Hypericin, Momordica charantia or bitter melon, garlic, grapefruit seed extract, mistletoe); biologicals (DHEA, thymus gland fractions, PCM-4, peptide T, shark cartilage, transfer factor, antineoplastons); pharmacologicals (DNCB, hydrogen peroxide, naltrexone); and homeopathies (low dose interferon, 714X, nosodes, sarcodes and homeopathics listed in the materia medica). Commonly used alternative modalities include hyperthermia, therapeutic touch, remote healing, Chinese herbal medicine, EM microcurrent devices, acupuncture, and homeopathy. The list of alternative therapies used to treat HIV/ AIDS grows monthly. To date, few have been subjected to evaluation for either safety or efficacy. A second aspect of the meaning of CAM is worth mentioning. Several therapies are used within and by the conventional medical community, but by their intended use they are called alternative. For example, psychotherapy is claimed by 34.7% of the Bastyr University Alternative Medical Care Outcomes in AIDS (AMCOA) cohort (n = 1675) as a CAM therapy for HIV or AIDS. Conventional use of psychotherapy is widespread in North America and Europe. Its intended use in this context is to assist HIV-infected individuals in coping with the disease and making appropriate psychological adaptations to their condition. Another use of psychotherapy in the conventional medical setting is to treat anxiety and depression in HIV-positive

10

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

HOW INTEGRATED IS THE PRACTICE? Frontier areas

Emerging areas

Integrating areas

• Frontier topics are those that challenge our conceptual and paradigmatic assumptions about the nature of biological or scientific reality. Examples include homeopathy, prayer, and healing practices such as therapeutic touch.

• Emerging CAM topics are those that involve common areas of interest for CAM and conventional medicine. Examples include acupuncture, herbalism (phytotherapy), and the use of high doses of combination nutritional supplements.

• Integrating topics are those often considered conventional but of interest to CAM practices. Examples include examining the mechanisms of action of popular dietary supplements, such as melatonin, DHEA, vitamins, minerals, antioxidants, and some behavioral medicine areas.

Figure 1-1 The spectrum of CAM. (From Jonas W: OAM: Investigating innovative approaches to health care, a report and plan for the Office ofAlternative Medicine, Bethesda, Md, 1998, National Institutes of Health.)

patients. The AMCOA study subjects also use psychotherapyas an intervention on the primary cause of the disease and to treat the immune deficit. The use of psychotherapy with the intention to "heal" HIV/ AIDS would be considered an alternative medicine. The addition of the word complementary, now in common parlance, implies that unconventional and conventional therapies and therapists can work best together. As alternative medicine becomes mainstream, the line between the two cultures is unclear. The use of multiple vitamins in therapeutic doses was once considered alternative but now is taken as common sense. Vitamin therapy is recommended by increasing numbers of conventionally trained physicians, as well as by alternative medicine practitioners. The increased use of multiple vitamin therapy was spurred on in part by the Barbara Abrams epidemiological study, showing how slowed progression to AIDS was associated with the use of daily multiple vitamins. s What constitutes complementary and alternative medicine will be in constant flux, with new CAM therapies continuing to emerge and some CAM therapies being included in conventional care and reimbursed by third-party payers. Nevertheless, CAM by definition will continue to challenge the assumptions ofthe dominant medical culture, whatever those assumptions may be.

methodological issues in evaluating whether CAM treatments work. The sections on treatments evaluate CAM approaches to treating the primary cause of HIV and central immune deficit, as well as treatments used to prevent and treat DIs and neoplasms. Contributing authors were sought whose clinical practice or scientific work encompassed clinical and laboratory outcomes that are important in understanding the experience of patients infected with HIV or those with AIDS, as well as the quantitative measures involved. CAM treatments include numerous and sometimes overlapping categories. In 1992 the DAM categorized the field ofCAM into seven areas that include (1) alternative systems of medical practice (e.g., traditional Chinese medicine, naturopathic medicine); (2) bioelectromagnetic applications; (3) diet, nutrition, lifestyle changes; (4) herbal medicine; (5) manual healing; (6) mind/body control; and (7) pharmacological and biological treatments. The integration of CAM and conventional medicine have been added as separate approaches to treatment. The chapters in this book represent some of the most current research in each of these seven areas of CAM in the treatment of HIV/AIDS.

HOW WE CHOSE THE TOPICS OF THIS BOOK

HOW THIS BOOK IS ORGANIZED This book focuses on treatment. It also offers perspectives on etiology, pathogenesis, and on the

The Bastyr University AIDS Research Center identified 1492 CAM therapies used for HIV/AIDS. There is a discrepancy between available scientific evidence and

AIDS and CAM

the prevalence of use among people affected with AIDS. The task facing the scientific and medical CAM community is to distinguish useful CAM therapies from marketing "hype" and self-delusion on the part of both well-meaning clinicians and patients. Early in its inception, the Bastyr AIDS Research Center9 articulated the criteria by which HIV/ AIDS alternative therapies were selected for evaluation, either by observational study or by clinical trial. Therapies were chosen that met one or more of the following criteria: (1) the particular CAM therapy was widely used; (2) patient or provider advocacy existed for the use of the therapy; (3) dramatic claims were made regarding the efficacy of the treatment; or (4) preliminary scientific evidence existed for the efficacy of the treatment. Sometimes attention is given to a CAM therapy that might be classified as an intellectual fad, or a "cure du jour." Examples were selected that have some scientific "staying power" or embody concepts persistent in CAM cultures. The two alternative medical systems discussed in this book, naturopathic medicine and Chinese medicine, were chosen because both the American naturopathic and Chinese medical communities came forward at the beginning of the AIDS epidemic to offer help to people infected with HIV. These two medical systems generated the most comprehensive CAM treatment for HIV/ AIDS. The chapters on the approach to treatment ofHIV/AlDS by alternative medical systems demonstrate the complexity of therapeutic thinking. For example, only two treatment principles are applied in conventional FDA-approved HIV/ AIDS treatments: (1) inactivate or destroy the virus, and (2) provide prophylaxis against Ols. Naturopathic medicine applies an array of principles to the treatment of HIV/ AIDS (see Chapter 20). Chinese medicine diagnoses HIV-infected patients by an entirely different and more conceptually complex system than conventional biomedicine. This book is not intended to offer comprehensive coverage of complementary and alternative medicine in HIV/ AIDS. The intent is to provide some of the best examples of alternative perspectives and treatments for HIV/ AIDS and to discuss some of the complex methodological issues pertinent to the scientific evaluation of CAM in AIDS or in any serious chronic disease. Not all evidence presented in this book for particular CAM approaches to HIV/ AIDS is published in peer-reviewed scientific medical journals. The field of CAM in the treatment of HIV/ AIDS research is in its infancy, and it is per-

11

haps premature to demand a surfeit of peer-reviewed papers from the CAM community. In the recent past, although ameliorated at present, a publication bias existed against CAM science, especially those approaches that do not conform to dominant biomedical theory about disease causation. Many CAM practitioners lack the research training necessary to execute well-designed research, let alone publish it or garner federal funding for it. Until recently there has been a dearth of funding for alternative medicine research. The availability of funding is growing but still lags behind the burgeoning interest in alternative medicine by both the public and the health care community.

CAVEATS This book is not intended as a clinical cookbook nor as a patient self-care guide. It is an attempt to illustrate some CAM concepts as they relate to HIV/AIDS and to summarize the current state of science in the field. The central issue concerning CAM therapies used in HIV/ AIDS is whether they are both safe and effective. It is often wrongly assumed that all natural substances and therefore most alternative therapies must be safe. Many CAM therapies derive from traditional medical systems that have been using particular herbs or medical procedures for centuries. Long-time traditional use can be taken as a suggestion of safety, but most therapies are not applied exactly as they have been traditionally applied. Other CAM therapies are more recently developed or invented, such as ozone, DNCB, and bioelectromagnetic therapies. Therefore we know less about short- or long-term consequences of their use. Ultimately, safety and efficacy should be established for each CAM therapy or combinations of CAM therapies in the same way that safety and efficacy are established for conventional pharmacologicals and procedures. Alternative medicine does not require an alternative science (see Chapter 1). With appropriate adaptations and modifications for the increased complexity of alternative medicine systems, such as combination therapy and acknowledgment of the significance of the placebo effect, the same standard scientific method should prevail. However, more sensitive measuring instruments may need to be developed, and methodologies may need to be refined. CAM takes it for granted that more may be going on in living systems than the currently-taught basic sciences might suggest.

12

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

THE CHANGING WORLD OF ALTERNATIVE MEDICINE There will always be a medical frontier or "fringe" of medicine that is its leading growth edge. There will always be fringe practitioners, theorists, and experimentalists excluded from the dominant medical culture who are pioneers. Sociologists have long pointed out the value of fringe groups in any aspect ofculture. As the current state of the science in HIV/ AIDS alternative medicine is examined and reported, the field is changing. As parts of CAM are mainstreamed, new CAM therapies and practitioners arise to take over the pioneering fringe. This is as it should be.

References 1. Vella S et al: Recent advances in antiretrovital therapy of HIV infection,] BioI Regul Homeost Agents 11(1-2):60-63, 1997. 2. Jonas W: OAM: Investigating innovative approaches to health care, a report and plan for the Office ofAlternative Medicine, Bethesda, Md, 1998, National Institutes of Health. 3. Eisenberg D, Kessler R, Foster C, et al: Unconventional medicine in the United States: Prevalence, costs, and patterns of use, N Engl] Med 328(4):248-252, 1993. 4. Eisenberg DM, Davis RB, Ettner SL, et al: Trends in alternative medicine use in the United States, 19901997: results of a follow-up national survey, ]AMA 280(18):1569-1575,1998. 5. Anderson WH et al: Patient use and assessment of conventional and alternative therapies for HIV infection and AIDS, AIDS 74:561-564, 1993. 6. O'Connor BB, Lazar )S, Anderson WH: Ethnographic study of HIV alternative therapies, Poster presentation, Eighth Int ConfAIDS 1992. 7. Mason F: The complementary therapies project's HIVtreatment survey, Toronto, Canada, 1995. 8. Abrams B, Duncan D, Hertz-Picciotro I: A prospective study ofdietary intake and AIDS in HIV-seropositive homosexual men,] Acquir Immune Deftc Syndr Hum Retrovirol 6(8):949-958, 1993. 9. Standish, L), Calabrese C, Reeves C, et al: A scientific plan for the evaluation of alternative medicine in HIV/AIDS, Altern Ther HealthMed 3(2):58-67,1997.

Referencesfor Table 1-1 Multicenter, randomized, placebo-controlled study of ditiocarb (Imuthiol) in human immunodeficiency virusinfected asymptomatic and minimally symptomatic patients, The HIV87 Study Group, AIDS Res Hum Retroviruses 9(1):83-89,1993.

Akerlund B, Tynell E, Bratt G, et al: N-Acetyleysteine treatment and the risk of toxic reactions to trimethoprimsulfamethoxazole in primary Pneumorystis carinii prophylaxis in HIV-infected patients,] Infect 35(2):143-147, 1997. Ancarani F, Veccia S, Giacometti A, et al: Zinc therapy in HIV-infected subjects, Int ConfAIDS 9( 1):493, 1993. Antoni MH, Cruess DG, Cruess S, et al: Cognitive-behavioral stress management intervention effects on anxiety, 24-hr urinary norepinephrine output, and T-cytoroxic/ suppressor cells over time among symptomatic HIVinfected gay men,] Consult Clin Psychol68( 1):31-45, 2000. Birk T), MacArthur RD, McGrady A, et al: Lack of effect of 12 weeks of massage therapy on immune function and quality oflife in HIV-infected persons, Int ConfAIDS 1996. Breitkreutz R, Pittack N, Nebe CT, et al: Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials [see comments],] Mol Med 78(1):55-62,2000. Burack )H, Cohen MR, Hahn )A, et al: Pilot randomized controlled trial of Chinese herbal treatment for HIVassociated symptoms,] Acquir Immune Deftc Syndr Hum RetroviroI12(4):386-393, 1996. Coates T), McKusick L, Kuno R, et al: Stress reduction training changed number ofsexual partners but not immune function in men with HIV, Am J Public Health 79(7):885887,1989. Conant MA, Calabrese LH, Thompson SE, et al: Maintenance of CD4 1 cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebocontrolled study, AIDS 6(11): 1335-1339, 1992. Coodley GO, Nelson HD, Loveless MO, et al: Beta-carotene in HIV infection,] Acquir Immune Deftc Syndr Hum RetroviroI6(3):272-276, 1993. Coodley GO, Coodley MK, Lusk R, et al: Beta-carotene in HIV infection: an extended evaluation, AIDS 10(9):967973,1996. Coutsoudis A, Bobat RA, Coovadia HM, et al: The effects of vitamin A supplementation on the morbidiry of children born to HIV-infected women, Am] Public Health 85(8 Pt 1):1076-1081, 1995. Cruess DG, Antoni MH, Kumar M, et al: Cognitive-behavioral stress management buffers decreases in dehydroepiandrosterone sulfate (DHEA-S) and increases in the cortisoljDHEA-S ratio and reduces mood disturbance and perceived stress among HIV-seropositive men, Psychoneuroendocrinology 4(5):537-549, 1999. De Simone C, Famularo G, Tzantzoglou S, et al: Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine, AIDS 8(5):655-660, 1994. Evans TG, McArdle M: Effect of oral dehydroepiandrosterone (DHEA) administration on acute phase reactants in advanced HIV-l-infected patients, Fourth Conference on Retroviruses and Opportunistic Infections 144, 1997.

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Falguera M, Perez-Mur J, Puig T, et al: Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity ofzidovudine, Eur] HaematoI55(2):97-102,1995. Fawzi WW, Msamanga GI, Spiegelman D, et al: Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-linfected women in Tanzania, Lancet 51(9114):14771482,1998. Fawzi WW, Msamanga G, Hunter D, et al: Randomized trial ofvitamin supplements in relation to vertical transmission of HIV-l in Tanzania,] Acquir Immune Deftc Syndr 23(3):246-254,2000. Fiala M, Cone LA, Sayre JW: Clinical benefits and recovery of delayed-type hypersensitivity in patients with AIDSrelated complex treated with IMREG-l or placebo, Int] Immunopharmacol13(7):999-1004,1991. Garber GE, Cameron DW, Hawley-Foss N, et al: The use of ozone-treated blood in the therapy ofHIV infection and immune disease: a pilot study of safety and efficacy, AIDS 5(8):981-984, 1991. Goodkin K, Feaster OJ, Asthana D, et al: A bereavement support group intervention is longitudinally associated with salutary effects on the CD4 cell count and number of physician visits, Clin Diagn Lab ImmunoI5(3):382-391, 1998. Gottlieb MS, Zackin RA, Fiala M, et al: Response to treatment with the leukocyte-derived immunomodulator IMREG-l in immunocompromised patients with AIDS-related complex. A multicenter, double-blind, placebo-controlled trial, Ann Intern Med 115(2):84-91, 1991. Heseltine PN, Goodkin K, AtkinsonJH, et al: Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment, Arch Neurol 55(1):41-51,1998. Humphrey JH, Quinn T, Fine 0, et al: Short-term effects of large-dose vitamin A supplementation on viral load and immune response in HIV-infected women,] Acquir Immune Deftc Syndr 20(1):44-51, 1999. Kennedy CM, Coutsoudis A, Kuhn L, et al: Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and postpartum among HIV-infected women,] Acquir Immune Deftc Syndr 24(1):37-44, 2000. Lang JM, Touraine JL, Trepo C, et al: Randomised, doubleblind, placebo-controlled trial of ditiocarb sodium (Imuthiol) in human immunodeficiency virus infection, Lancet 2(8613):702-706, 1988. LaPerriere AR, Antoni MH, Schneiderman N, et al: Exercise intervention attenuates emotional distress and natural killer cell decrements following notification of positive serologic status for HIV-l, Biofeedback Self-Regulation 15(3):229-242, 1990.

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Look MP, RockstrohJK, Rao GS, et al: Sodium selenite and N-Acetylcysteine in antiretroviral-naive HIV-l-infected patients: a randomized, controlled pilot study, Eur] Clin Invest 28(5):389-397, 1998. Montaner JS, Gill J, Singer J, et al: Double-blind placebocontrolled pilot trial ofacemannan in advanced human immunodeficiency virus disease,] Acquir Immune Deftc Syndr Hum RetroviroI12(2):153-157, 1996. Navarette MS, Gharakhanian S, Cardon B, et al: Vitamin B12 supplements in patients treated with zidovudine, Int ConfAIDS 5:338, 1989. Perna FM, LaPerriere A, Klimas N, et al: Cardiopulmonary and CD4 cell changes in response to exercise training in early symptomatic HIV infection, Med Sci Sports Exerc 31(7):973-979, 1999. Pichard C, Sudre P, Karsegard V, et al: A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and omega-3 fatty acids in HIV-infected patients, Swiss HIV Cohort Study, AIDS 12(1):53-63, 1998. Reisinger EC, Kern P, Ernst M, et al: Inhibition ofHIV progression by dithiocarb, German DTC Study Group, Lancet 335(8691):679-682, 1990. Rigsby LW, Dishman RK, Jackson AW, et al: Effects of exercise training on men seropositive for the human immunodeficiency virus-I, Med Sci Sports Exerc 24(1):6-12, 1992. Sankary T: Controlled clinical trial of anginlyc, Chinese herbal immune enhancer, in HIV seropositives, Int Conf AIDS 5:496, 1989. Scafidi F, Field T: Massage therapy improves behavior in neonates born to HIV-positive mothers,] Pediatr Psychol 21(6):889-897,1996. Semba RD, Lyles CM, MargolickJB, et al: Vitamin A supplementation and human immunodeficiency virus load in injection drug users,] Infect Dis 177(3):611-616, 1998. Shlay JC, Chaloner K, Max MB, et al: Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial, Terry Beirn Community Programs for Clinical Research on AIDS [see comments],]AMA 280(18): 1590-1595, 1998. Simpson OM, Dorfman 0, Olney RK, et al: Peptide T in the treatment of painful distal neuropathy associated with AIDS: results ofa placebo-controlled trial, The Peptide T Neuropathy Study Group, Neurology 47(5):1254-1259, 1996. Spence DW, Galantino ML, Mossberg KA, et al: Progressive resistance exercise: effect on muscle function and anthropometry ofa select AIDS population, Arch Phys Med Rehabil71(9):644-648, 1990. Stringer WW, Berezovskaya M, O'Brien WA, et al: The effect of exercise training on aerobic fitness, immune indices, and quality oflife in HIV-positive patients, Med Sci Sports Exer30(1):1l-16,1998.

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Taylor DN: Effects of a behavioral stress-management program on anxiety, mood, self-esteem, and T-cell count in HIV-positive men, Psychol Rep 76(2):451-457, 1995. Walmsley SL, Khorasheh S, Singer j, et al: A randomized trial of N-Acetylcysteine for prevention of trimethoprimsulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057), Canadian HIV Trials Network 057 Study Group, J Acquir

Immune Deftc Syndr Hum RetrovirolI9(5):498-505, 1998.

Weber R, Christen L, Loy M, et al: Randomized, placebocontrolled trial of Chinese herb therapy for HIVI-infected individuals, J Acquir Immune Deftc Syndr 22(1):56-64, 1999. Weerts D, De Wit S, Gerard M, et al: A phase II study of carrisyn (C) (Acemannan) alone and with AZT among symptomatic and asymptomatic HIV patients, Int Can! AIDS 6(3):203, 1990.

Research Issues in CAM and HIV/AIDS CAR LaC A LA B RES E MARY

LOU GALANTINO

esearchers have been increasingly interested in complementary and alternative medicine since the field was legitimized as an arena of investigation by the establishment in 1992 of the Office ofAlternative Medicine (OAM) at the National Institutes of Health (NIH). Complementary and alternative medicine (CAM) use for all medical conditions is growing significantly in the United States and other countries. There is an increasing social impetus to determine the safety, effectiveness, and cost-effectiveness of CAM. A concomitant increase in public and private attention and funds is invested in research in this area. The first question the consumer asks is, "Does CAM work?" The medical professional asks, "Can CAM meet the standard of proof of modern research?" The following range of ques-

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tions applies equally to all brands of medicine and contributes to evidence-based medical practice: 1. Safety evidence-Is the practice safe? 2. Experimental evidence-Is the practice efficacious when examined experimentally? 3. Clinical practice evidence-Is the practice effective when applied clinically? 4. Comparative evidence-Is it the best practice for the problem? 5. Rational evidence-Is the practice rational, progressive, and contributing to medical and scientific understanding? 6. Demand evidence-Do consumers and practitioners want the practice? 7. Satisfaction evidence-Is it meeting the expectations of patients and practitioners?

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8. Cost evidence-Is the practice cost-effective? 9. Meaning evidence-Is the practice the right one for the individual? The kinds ofevidence listed should be part ofa research agenda when possible, regardless of whether the clinical orientation is CAM or conventional.! The use ofall these types is valuable not only to federal and state agencies that regulate practices and insurance companies that attempt to regulate health economics but also to caregivers and consumers using CAM. CAM adherents want more research done but meet obstacles early; CAM opponents feel that funding for research is unjustified and that the attention it brings merely gives consumers false hope. With the successes of protease inhibitors in the late 1990s, attention to CAM in the treatment ofAIDS has relaxed somewhat, but the number of HIV-positive users did not significantly diminish and resurged with the emergence of the drawbacks of highly active antiretroviral therapy (HAART). The difficulties of research in AIDS, whether in conventional or alternative medicine, are numerous. The putative causative agent-the human immunodeficiency virus (HIV)-is well protected and highly mutable. There are numerous contributory causes to the immunological pathogenesis. A number ofblockable molecular targets have been identified in the virus, and some are being exploited pharmaceutically, but a cure is as yet out of reach. The search for a vaccine with an ability to effectively stimulate either an antibody or a cellular immunity against HIV has not yet been productive. The appropriate immunological targets for potentially supportive therapeutics have little consensus surrounding them. Stimulation of CD4+ lymphocytes, for example, holds the potential danger of stimulating the production of the virus in infected cells, since the virus uses the replicative machinery of the cell itself. Some researchers hypothesize that the associated opportunistic infections (Ols) are precipitated by the senescence of the immune system, which is overstimulated from fighting the virus, and that further stimulation of the immune system would ultimately prove futile. 2 The complications of the disease are numerous. Because separate drug regimens of varying effectiveness for each separate condition exist, distinguishing the effects of a single intervention is difficult. In addition, deleterious drug interactions are increasingly likely with additional treatments. Now that there are some effective therapeutics for HIV infection, the 10-

gistics and ethics of patient recruitment for clinical trials are compounded. Even when trials are conducted, the hard endpoints of viral load and CD4 + lymphocyte levels are only substitute measures for the progress of the disease and the patient's quality of life (QOL). No studies have yet been done on the number ofquality-adjusted life years saved by treatment of the putative causative infection by current antiretroviral therapy (ART) or for repair of the central immune deficit. Aside from these difficulties in AIDS research, greater problems exist in attempting to determine if CAM can playa role in ameliorating or even curing AIDS. Although the view exists that CAM research has no particular problems,3 the research establishment is largely unable to affirm or deny the benefits of CAM in the treatment of AIDS. Of the research domains-qualitative, laboratory, epidemiological, and clinical-ofCAMs, we focus here on research on the evaluation of clinical outcomes. Clinical studies are the most problematic but also the most fruitful, definitive, and urgent. By necessity we must discuss the other research domains when their interrelationship with clinical studies is unavoidable.

THE PROMISE The experienced CAM practitioner and other adherents answer the question "Does CAM work?" with an almost unequivocal "yes." Several studies have shown high rates of CAM use among HIV-positive persons. At Bastyr University a survey conducted of 120 selfdescribed practitioners of alternative medicine revealed that these providers (MDs, NOs, DCs, acupuncturists, herbalists, and so forth) treat patients at all stages ofHIV disease with a variety ofCAM practices. 4 Over 90% of the surveyed providers ofalternative therapies for HIV/ AIDS claimed that their therapies were "somewhat" to "very effective" at all disease stages and on all disease measures, including symptom management (96%), maintaining QOL (98%), raising or maintaining CD4+ lymphocyte levels (66%), slowing progression to AIDS (69%), and extending survival (73%). The providers in the survey were credentialed (80% held state licenses to practice), had substantial experience treating HIV disease (a mean of 6.5 years experience), and were generally willing and able to participate in studies that examined their claims. Some evidence shows that specific CAM treatments are effective in managing AIDS (see Chapter 20).

CHAPTER 1 Research Issues in CAM and HIV/AIDS

THE CHALLENGES The Congressional mandate in the establishment of the OAM, now the National Center for CAM (NCCAM), was to screen and evaluate the most promising unconventional medical practices to develop reliable evidence as a guide to public policy. Given claims and preliminary evidence in the desperate situation of a worldwide pandemic, it is worthwhile to devote a small portion ofsocietal resources to the fields of knowledge peripheral to orthodox approaches in response to the AIDS crisis. If this can be done, valuable treatments and approaches that would not otherwise be explored could be generalized to standard practice in AIDS medicine.

The Breadth of the Problem To determine if CAM is effective, testworthy CAM practices must be standardized. Complementary and alternative medicines are immensely varied. There are perhaps 5000 plants in the world's herbal pharmacopeias, perhaps 2000 homeopathic remedies, hundreds of natural product medicinals, and at least hundreds of identifiable manipulative practices, dietary practices, psychospiritual approaches, and entire systems of medicine with their own nosologies and conceptions of etiology. In a thoroughgoing evaluation each of these would be parsed, and those relevant to AIDS would be tested. The breadth of content is not only theoretical. In our nationwide longitudinal observational study of 1689 HIV-positive people who were self-identified as using alternative medicine for HIV/ AIDS, we categorized possible alternative treatments into different types of providers, substances, and treatment activities garnered from scientific literature, newsletters, clinicians, and buyers clubs.s We felt that we were being comprehensive in listing 21 alternative provider types, 86 substances, and 46 treatment activities and were amazed to see our participants add an additional 98 provider types, 1124 substances, and 236 treatment activities to the list. Thus between October 1995 and December 1997, the cohort reported the use of a total of 1492 alternative treatments provided by 119 different provider types for HIV disease. In addition to this imaginative and gritty response, alternative approaches to the AIDS epidemic are being developed simultaneously under urgent circumstances in intellectually and economically divergent

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cultures throughout the world. This book barely scratches the surface in providing an overview of the field's possibilities.

The Lack of Preliminary Bibliographical Data A bibliographical search of the accumulated scientific literature is usually the beginning of the pursuit of potentially worthwhile treatments. Unfortunately, the literature on CAM is sparse. Literature on AIDS treatments is especially poor since AIDS is a new disease without the centuries of empirical experience of traditional healers frequently found in CAM treatments. The paucity of CAM literature is due partly to past publication bias against alternative medicine. Peerreview boards are composed ofconventionally trained scientists who reject submissions that present a contradiction to the orthodox scientific knowledge base. Orthodoxies as systems are necessarily well organized to resist evidence of theoretically aberrant experiences. Although this prejudice may be overcome by several lines ofevidence cogently presented to editors, such a scientific campaign is unlikely for most CAMs that do not have the cadres ofscientists needed to design and perform the many experiments that are necessary to overcome divergent orthodox scientific opinion. Simultaneously, there is little resistance to the publication of poorly designed studies refuting claims of the effectiveness of alternative treatment. Recently, a first-rank medical journal, as evidence against CAM effectiveness, published a study designed by a fourth-grade student and a well-known opponent ofalternative medicine. They performed an experiment refuting a tenet not even held by the alternative treatment therapy that was purported to be studied. 6 The scientific media has been much more receptive to discussion and evidence in CAM in the last few years, but the accumulation of studies is still small. The more germane problem regarding the lack ofCAM data at this point is the lack of CAM research capacity.

The Lack of Research In frastru cture Investigation in CAM practice has suffered from a relative lack of trained scientists and a lack offunding aris-

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ing from corporate pharmaceutical research. Modern pharmaceutical research depends on patentability for profitability, and CAMs typically fail the legal tests for patentability. Thus molecular pharmaceutical medicines have the proper economic incentives for development by profit-driven industries while taking advantage of federal- and foundation-funded investigator-driven basic science. Although drug manufacturers are tempted by the economic carrot, they are also driven by regulatoty necessity. CAM research incentives are missing at both ends of the process. Basic research infrastructure for CAM is also missing in the nonprofit development arena because in recent history, applications for funding for research studies, research training, and research facilities for alternative medicine were likely to be rejected by scientific review boards of foundations and the Public Health Service (PHS). Review boards are composed of scientists who are dedicated to an orthodox body of knowledge. Clearly the theory and practice from which CAMs spring are not orthodox by definition. Despite an activist climate in favor ofCAM treatments in AIDS research and high CAM use among AIDS patients, the NIH budget had no significant funding of the study of alternative medicine for AIDS until the establishment of Bastyr University's AIDS Research Center in 1994. Federal research dollars devoted to AIDS make it the number-one disease in funding perdisease-caused death at about 12% of the 1997 NIH budget. The 3% ofOAM's 1997 budget of$12 million devoted to CAM in the treatment of AIDS was thus 0.0003% of the NIH AIDS budget in the best annual funding scenario in modern history. In Great Britain the situation is somewhat better, but alternative medicine research recently received only 0.08% ofNational Health Service (NHS) research spending,? Finally, the impetus to do research is not universal among alternative advocates. Some CAM practitioners, although true believers in alternative medicine, feel that they have nothing to prove. Others, who are more inclined to the real-time study of their own therapies, may choose case histories and observational studies as ethically preferable to more convincing methods that are seen as objectifying and manipulating patients. The scientific and ethical interface is a subtle one in modern medical research and has taken decades, even centuries, to develop its safeguards. Its mores are learned through institutional enculturation and experience in applying ethical principles to particular scientific problems. Ethical boards for research have only recently become common in CAM institutions.

Ethics The Nuremberg trials of 1946 defined the ultimate responsibility of the physician to engage only a wellinformed, consenting patient in experimental procedures (Nuremberg Code of 1947). Similar ethical standards were promulgated worldwide with the Declaration of Helsinki in 1964. The Belmont Report (1975), on which US human research policy rests, emphasized the difference between therapeutic research and research unrelated to improving the patient's state of health (the principle ofbeneficence) and respecting the autonomy of the subject. These principles are no less applicable to research with human subjects for CAM as for conventional medicine. Yet ethical regulation of research arose from social values, including the clinical values ofmedical practice. The CAM professions are developing an ethical research structure, including institutional misconduct policies and ethical review boards, consistent with both their own professional context and current ethical controls for medical research that permits research consistent with CAM practice. s Ethical control depends partly on preliminary safety information. What constitutes evidence of acceptable risk may be at issue between the two cultures, with animal testing and Phase I trials typically required by conventional authorities versus the evidence ofcommon use usually presented by CAM practitioners. A design standard that calls for the need to withhold a known effective treatment may also make some CAM investigations impossible when seen from the point of view of conventional medical institutions. Some investigators suggest developing alternative trial designs to resolve current conflicts between the ethics and science even of conventional drug trials. 9 However, the autonomy of patients who reject or fail conventional interventions also needs to be respected. Such patients may provide a volunteer pool for the investigation of CAMs. When the patients are children or other dependent individuals, their lack of autonomy compounds the ethical issue in clinical study, since others may need to make the crucial decisions for them. Yet in the case of pediatrics, pressure is growing to test treatments in children if the treatments are to be used in children. 10 The principle of beneficence in this instance precludes research that does not bear the possibility of therapeutic advantage for the subject. The problem of pediatric trials is common to both CAM and conventional medicine but may prove more difficult to solve with CAM.

CHAPTER 1 Research Issues in CAM and HIV/AIDS

Methodological Difficulties

in CAM Clinical research methodology has some difficulties with several characteristics of CAMs. Study designs can often accommodate these difficulties, but they must be well understood before research credible to all stakeholders will have been done.

Variability of CAM Interventions Besides the contextual problems of the paucity of literature, funding, competent investigators, and other structural impediments in the field, inherent methodological difficulties exist in alternative medicine research. One is the variability ofspecific CAM interventions. Since replicability is a hallmark of the scientific method, specifically what is tested-whether a substance, a treatment procedure, or a system ofpracticeneeds to be defined, described, and stabilized so that it can be delivered reliably from patient to patient and study to study so that one can make a generalization about the results. Funders of research intend to shape social policy by the results of their support, and they need some assurance of replicability. But in the history of research in alternative medicine, the definition of a practice has typically been ad hoc per study and has varied with the perspectives and affiliations of authors, making metanalyses futile. ll The standards of complementary medicine tend to be organic and in flux, which is to be expected of a nascent science and industry. From the manufacturing practices for botanical preparations to educational standards for acupuncturists, the definitions and qualities of most CAMs have not achieved anything approaching consensus. Botanical medicine, as an example, represents a relatively simple problem of nonstandardization among alternative medicines. With herbs it is quite possible to perform a single-agent controlled trial in a specific disease, but numerous choices need to be made regarding the intervention. Problems in studies begin with the verification of plant species used, conditions under which the plant is grown and harvested, and the storage and stability of active compounds. There are choices of whether to use the whole plant, particular parts, various crude extracts, or a specific chemical constituent that may be concentrated in various ways and to varying degrees of purity. Crude fresh extracts, to which many clinical herbalists are partial, are susceptible to deterioration. In the most sophisticated systems of botanical medicine preparation, a product

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is standardized for a number of ingredients-for some guaranteeing a minimum concentration and for others a maximum concentration. This is true of the Ginkgo biloba extract, for example, which has been the most studied: Standardizing constituents may present complications. For instance, active ingredients in plants are often classes of molecules, like polysaccharides, saponins, or terpenes, which are difficult to distinguish in biological activity. Different compounds in a single species may have similar or possibly complementary effects, such as the polysaccharides and isobutylamides in Echinacea spp. During in vitro assays that guide fractionation of the crude extract toward a single active molecule, it is not uncommon for activity to increase but then diminish as an identified molecular species reaches greater purity, as was the case with the terpenes of Andrographis paniculata, t which have an influence in cell signaling. When such problems are addressed, these levels of standardization test the industrialization of botanical medicine rather than its roots and do not answer the questions ofwhether the more commonly used crude extracts or powdered herbs produce the hoped-for clinical benefits. The problems in botanical research are compounded in other fields of CAM research. Nutrition, for example, can be divided into dietary practices and nutritional supplements. Studies in dietary interventions are demanding. The gold standard for dietary intervention is a residential facility to maintain adherence to the therapeutic regimen, which is an expensive solution, and recruits may be difficult to find. Other populations with controllable diets include the armed forces, prisons, retirement homes, and schools, but ethical review would need to be vigorous. Often in dietary studies a long observation time is needed because diets are often intended as preventives or restoratives, for which clinical outcomes would take a length of time to observe. Finding an appropriate comparison control may also be difficult. Nutritional supplements may be simple (e.g., individual nutrients such as vitamins, minerals, or other single-molecule agents) or complex interventions. Individual nutrients are well known and have been evaluated in general human health for many years. When they are efficacious, they are likely to work in a carefully selected clinical population with idiosyncratic genetically or *Egb761, Schwabe GmbH. tAndroVir, Paracelsian, Inc.

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environmentally determined needs. Therefore clinical study typically calls for either extensive diagnostic studies or very large numbers ofsubjects (as relatively few will show clinical response). Complex nutritional supplements are special foods like probiotics (live, purportedly health-enhancing bacteria) or algae. Studies in these types of interventions have complications similar to botanical medicine studies.

Nonmaterial Interventions: Procedural, Verbal, and Behavioral Medicine Both botanical medicine and nutrition are material interventions that, although there are difficulties involved, frequently have well-accepted research models. An adaptation of pharmaceutical clinical research methods may be made with some compromises. Nonmaterial interventions, such as manipulation, exercise, acupuncture and other forms of point work, or psychospiritual treatment, are more problematic. Some simple improvements in clinical research methods have gradually been accepted by both critics and adherents of various CAMs. A blind experiment can be maintained if the therapist and the assessor of health status and outcome see the subject independently. To increase the certainty that a treatment is given every chance to be effective, a rater whose expertise is similar to that of the therapist determines whether the treatment has been correctly applied. For example, two osteopathic doctors trained in the same approach to CranioSacral Therapy see the subject in succession. One treats the subject and the other determines if the subject has improved according to the tenets of the practice before the subject goes on to biopsychosocial medical evaluation. Controls may be difficult to select ifa blind experiment is the goal. But progress has been made, even in acupuncture,J2 which has been notoriously difficult to blind. Placebo controls may be difficult to choose, such as with bed rest or eating more vegetables. Randomization to a waiting list or standard care is available, although the level of placebo effect will differ if the two interventions are grossly different or are delivered in different contexts. The increasingly popular electromagnetic (EM) treatments should be easy to test against a placebo as their immediate effects are not apparent to the subject, and the magnetic field can simply be turned off or the magnets removed and replaced by a look-alike. A subject determined to find out what treatment he or she is using, however, can figure it out under most circumstances, ifhe or she has time and opportunity.

CAM use of psychotherapies may be said to be those that are "offlabel" for psychotherapy, that is, intended to have effects on physical rather than on mental illnesses. It may be easier to perform tests of hypotheses related to such uses of psychotherapy, since measures of physical disease may be more reliable than psychological outcome measures. The preceding considerations on the variability of the intervention apply. It is difficult to control the application ofa particular psychological intervention because its application is hard to separate from the effect of the therapist. The specificity of practitioner-patient interaction is also troublesome if the experimenter, rather than the therapist, determines the result of the particular psychotherapy; this may result from the extended exposure and greater rapport that is established between therapist and patient. With few exceptions, little has been done on health outcomes consequent to psychological interventions in AIDS (see Chapter 18). If psychotherapy is expanded to include spiritual interventions (such as personal prayer, meditation, or religious practice or belief), an arena often of significant interest to CAM holistic practitioners and adherents, the research record on interventions is practically nil. The use of spiritual experience is likely to be idiosyncratic or culture specific. Definitions ofspirituality in medical literature refer to hope and meaning, a personal relationship with God,13 serenity,14 connectedness-all perhaps related to the patient's state of consciousness. A number of thinkers bemoan the lack ofdefinition in this area. IS Although efforts to present cogent, broadly acceptable definitions are made,16,17 they have not been widely successful. Only in the fourth edition of the Diagnostic and Statistical Manual-W (DSM-W) (1995) was the possibility ofa religious or spiritual problem even recognized. 18 In medical literature, most references to spirituality come from the nursing field. Relatively little interest has been displayed in the effect of different spiritual interventions on health. Although some traditional medicine practitioners seek to promote spirituality among AIDS patients l9 and some relate the hardiness ofpeople with AIDS to their spirituality,20 almost none seriously consider the possibility of a spiritual intervention,21 and no recent studies have considered the effect ofspiritual intervention on health outcome in AIDS. Usually, spirituality in AIDS is seen as a coping mechanism. 22 Another aspect of the spiritually therapeutic refers not to the influence of a patient's internal states on

CHAPTER 1 Research Issues in CAM and HIV/ AIDS

health outcomes but to the intentional therapeutic action, not mediated by language or any well-known material force, ofone individual on another. This is sometimes called psychic healing or simply healing. Prayer for a patient by others may also be included here. 23 Variations may include Therapeutic Touch (IT), laying on of hands, Reiki,]ohrei,24 psychic surgery, mental healing, and other types of paranormal healing. If the intent is to determine if these techniques have an effect on disease, there exist no more particular difficulties to researching studies other than are already addressed here. Design differences may be called for if the therapists were special versus ordinary people or ifrhe healing energy is directed or willed versus invoked (as from God or spirits). Homeopathy bridges material and nonmaterial interventions. Several treatment approaches exist in homeopathy: constitutional prescribing, acute treatment, proprietary combinations, nosodes, Bach Flower Remedies, Schussler Cell Salts, and so forth. In classical constitutional homeopathic theory, treatment outcome is exquisitely sensitive to the precise remedy chosen for an individual, and prescription errors may be frequent. An extensive case history must be taken and a remedy found before prescription. Then the prescriber proceeds from the clinical outcomes to determine if the correct remedy was chosen. Thus only expert prescribers should be research clinicians, and the likelihood of frequent prescription errors must be considered in design.

Combination Treatment As complex as these problems are, they pale in the face of the tendency among experienced herbalists, for example, ofall cultures to use botanical medicines in combinations individualized for a particular case. This almost universal practice of combination treatments complicates, by order ofdifficulty, the research problems of standardization, clinical indications, therapeutic targets, and potential toxicities. Individualization and combination are ubiquitous among alternative medicine practices. In a condition with the broad impact and variable expression of AIDS, they are almost inevitable. The tendency toward eclectic combination culminates in therapies such as magnetically enhanced homeopathic remedies (MEHR), in which the interaction of therapeutic cultures (with intriguing preliminary evidence in HIV disease in its favor) results in homeopathically potentized herbal preparations that are injected into the patient at spe-

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cific points through a magnetic field. Combination treatment may be critical to the success of those regimens that use them. Single natural agents may have a true effect small enough that a very large patient sample size would be required to detect a difference. Several agents acting together, however, especially if by different mechanisms, may have a cumulative or synergetic effect of a size that may be more readily detectable in clinical trials. Combination treatment may also give the CAM practitioner additional latitude in choosing the correct remedy for a patient's condition, thereby increasing the success rate of treatment. The possibility of adverse events (AEs), however, may rise with combinations.

Individualization The specificity ofthe constitutional homeopathic remedy introduces the idea of individualization of treatment regimes. Individualization means that remedies are not prescribed solely on the basis ofa single disease category but on other characteristics of the patient. Such characteristics may be transient or constitutional, or they may be chosen as representative of the entire constellation of the patient's health problems and health strengths. The lack offit between a person's health syndrome and a conventional disease modelexpressed perhaps in the inability or reluctance of a conventional practitioner to diagnose a particular health problem-may be the very reason a patient turns to CAM. If a medical system does not recognize an entity, it is unlikely to have an effective therapy for it. The complaint will be managed as something else, resulting in ineffective treatment while exposing the patient to the side effects of the applied treatment. Conversely, a medical system that provides an adequate explanatory model for a patient's experience of his or her symptoms, their origin, and their aggravators and ameliorators has a better chance of having effective treatment or condition management. Thus individualization of treatment is a strength of CAM rather than merely a research problem. If the need for individualization where it is called for in the CAM therapeutic system is neglected in research design, the design will fail to apply the CAM as practiced and will fail to evaluate its potential benefit. A hallmark of medical science is replicability of results obtained with the same intervention. It may be that conventional scientists are reluctant to engage in methods that evaluate an individualized treatment because using such methods implies a rejection of the fundamental

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doctrine of replicability. In reality, however, no two cases are alike, and the effort to treat patients and their health as if they were engineering materials is a bare approximation of reality-a convenience for practitioners and their body of knowledge.

Medical Systems The most extreme examples of combination treatment, and concomitantly the most difficult research problems, arise when entire medical systems are to be evaluated. Oriental medicine is an interlocking set of systems with a long history and a well-developed and highly specific body of theory. Some difficulties in acupuncture research have been mentioned. But acupuncture is not practiced alone; rather it is a physical therapy of Chinese medicine. The entire practice includes herbs (commonly in combination), foods, and other physical treatments. Chinese medicine has ramified throughout Asia, Europe, and North America with different styles developing such as traditional Chinese medicine (TCM), Five Element, Japanese acupuncture, and Kanpo. In any of these, the nosology (the array of described pathology) does not coincide with Western pathology. A Western audience, especially a scientific one, is rarely impressed by a superior treatment to correct "Stomach/Spleen disharmony" especially if intermediate markers may be tongue and pulse diagnosis. Proper treatment needs to be individualized and based on the Oriental diagnosis instead of on the diagnosis of AIDS. It is possible to approximately translate syndromes of one system into those of another, but it must be understood that this will decrease the likelihood of applying the correct treatment from one system (Oriental) when its diagnosis is compromised by guidance from principles of a second system (Western). Translation may take place by assigning a Western disease to several Oriental syndromes and then choosing the appropriate treatment for the patient's particular expression of the Western disease. Treatment algorithms that indicate specific Oriental treatments for the Oriental diagnoses that overlap Western diseases may be developed by expert Oriental practitioners who have cross-training in Western medicine. Similarly addressed would be Ayurveda, Unani, the whole practices ofshamans and curanderas,25 and other animistic and vitalistic traditions. Naturopathy, osteopathy, and chiropractic, although removed somewhat in practice from their historical origins, also need to be treated as whole systems.

Thus treatments from systems of medicine are combined and individualized based on the rules of the alternative practice being studied rather than on an allopathic approach to conventional Western disease entities. An allopathic approach implies directly contravening or suppressing a disordered physiological parameter or infectious agent. It is an approach that provides impressive results, at least in the short run, partly because substitute measures for human health improvement are derived from the reductionistic components within its theoretical underpinnings. Alternative practitioners frequently refer to a rationale of balancing, modulation, supporting, and detoxification. Quantifiable measures for these possibly metaphorical goals have not been developed. Despite the lapse of good measures for such outcomes, distorting a practice to fit current research or disease models and measures models may miss possible benefits of CAMs. CAMs that are not evaluated by their own principles cannot be confidently discarded as useless.

Holism Holism in health research refers to all parameters of human health: physical, psychological, spiritual, social, and environmental. In a research model, holism may be applied to the intervention, as well as to the outcomes. An intervention intended to respond only to a disease entity is not a holistic response nor is it holistic to measure only disease-specific outcomes. While a truly holistic model must contain the reductionistic components to examine the relationship between parts and wholes, questions emerging from a holistic paradigm would be difficult to investigate in vitro. CAM adherents often claim that particular CAMs affect broad parameters of human function such as energy level, immune function, healing capacity, and sense ofwell-being. They are theorized to have less symptom-specific amelioration but more general health benefits. These kinds of outcomes are difficult to measure yet will have great impact on human suffering, as well as important economic effects in the use of health care and lost productivity. Since holism implies a reference to the whole of life, studies that intend to measure such values may require extended trials (and substantial expense). When a health care practice is intended to affect the whole being and guide a person toward optimal health, a failure to measure whole health outcomes is a failure to fully evaluate the CAM under investiga-

CHAPTER 1

tion. Some critics say that a holistic paradigm cannot be researched at all because research is necessarily reductionistic. 26 To investigate holistic practice, many compromises in the reductionistic gold standard need to be made. If there is to be a reasonable approach to the investigation of holistic medicine, at least one side of the intervention-outcome variables of scientific experimentation needs to be holistically conceived. Fortunately, the development of broad holistic healthoutcome measures has advanced since the 1970s. Multifactorial holistic interventions, however, have been rarely investigated, and related proposals have suffered from even greater discrimination by research establishments than have simple materially based CAMs.

Intention A confounder in a clinical trial is an apparent therapeutic effect that is attributable to a factor associated with the treatment rather than to the test treatment itself. Confounding is a risk inherent to all research. It is why randomization, blinding, and objective measures are valuable in distinguishing therapeutic differences among medications. The most honest scientists may have conscious or unconcious behaviors that modify study results. However, an important confounder that is integral to some CAMs is intentionality. The scientific literature may refer to this as mental or psychic healing and does not always attribute it to ordinary practitioners. Little is written on the capacity of intention to influence physical outcomes; in fact, critics implicitly reject the idea based on Cartesian mind-body duality. Nevertheless, a number of studies indicate its existence. 27•28 Studies of the effect of prayer are also relevant here 23 and raise the possibility that specific kinds of intentionality may make a difference. Studies that blind the practitioner and patient decrease or eliminate the possibility that intentionality will contribute to a positive outcome. Yet CAM theories explicitly accommodate bonding and expectation as contributors to outcome. 29 Intentionality, if it is effective at improving health outcomes, is a difficulty only for research. In clinical practice, therapist intention, if actually efficacious at improving health outcomes, is a wholly nontoxic intervention exercised by all healers-it is in fact the sine qua non of healers. It is well accepted that orthodox medical care is practiced in a medical culture where practitioners and patients have certain roles and expectations that rein-

Research Issues in CAM and HIV/AIDS

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force expected outcomes. Qualitative ethnographical research is needed to understand the consequences of diverse explanatory models and meanings of health and illness for patient-provider communication, adherence with professional recommendations, and satisfaction with care. to Some studies indicate that good physician-patient communication results in better medical outcomes. 3D Various alternative medicine systems have a culture with similarly reinforcing behaviors and beliefs for expected outcomes. Those who refuse to be randomized may likely have a therapeutic orientation that works synergistically with the physical effects of a preferred medicine. The tests of real interest to policymakers are not simply those that determine whether a CAM practice works for anyone to whom it is applied, but those that determine whether it works (and is cost-effective) among those who choose it. A study design that could determine the value of the availability ofalternative care in those who choose it rather than when it is assigned is to randomize to either randomization to alternative versus conventional care or to a choice of alternative or conventional care. Such a four-group trial would compare the effects of the different treatments among those who chose them versus those who were assigned to them.

SOME RESPONSES TO THE PROBLEMS Current circumstances present a wide field of choices to study in CAM medicine, few of which have much preliminary or distinguishing data. When this is combined with the paucity of research resources, picking the right questions-significant, answerable, and feasible to investigate-is a high art. A few principles suggested here may increase the quantity ofsignificant research in CAMs.

Define the Interventions First, definition and description are needed to identify and render various therapies replicably deliverable. Descriptive and qualitative research, although perhaps not as satisfying or as politically popular as outcomes testing, is necessary for serious investigation of individual treatments, systems, and approaches. Ongoing definition informs the

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conventional research establishment (e.g., NIH, PHS, medical academics, and the pharmaceutical and health insurance industries) so that the integration of CAMs with the dominant medical research and practice paradigm is facilitated. It allows CAM practitioners to focus on interventions that are replicable and transferable. These are the only interventions that are likely to be adopted in the increasingly industrialized-and now incorporated-health system.

Screen the Possibilities to Select the Best Candidates Asking the right question is always the most difficult problem in research. This is especially true for CAM, since its research questions need to be refined. All of the problems of doing research in conventional biomedicine apply, without the guidelines that biomedical theory has built over the last two centuries. Although some CAM interventions are obvious choices for testing in other medical conditions, fewer such indicators exist in AIDS partly because it is a new disease without a long history of traditional treatment. In general, clinical screens must be used to generate worthwhile hypotheses for further testing. Clinical outcomes are more relevant at this point than clinical mechanisms for three reasons: (1) we do not know the clinical mechanisms for most CAMs, (2) we may not have the tools to measure the mechanisms unique to alternative medicines, and (3) the interaction questions are often too complex to parse. Once a commitment to clinical methods is made, a balance of tools should be favored that has a broad perspective (e.g., qualitative research, observational studies, small comparison trials) rather than just a focus on a few narrow, randomized trials. When with a new field, it is useful to begin with a wide-angle detection system that changes facultatively to a highprecision instrument to test specific examples as supportive evidence emerges. High assurance at first pass is not needed; rather, a ranked order oflikely positive effects for the greatest health benefit provides the best guidance.

Use All of the Methods of Science One of the most important research methods to pursue is the single-agent randomized, controlled trial

(RCT). Single-agent RCTs provide empirical scientific evidence. Controlled clinical trials are the only legal basis for the Federal Drug Administration (FDA) to conclude that a new drug has shown "substantial evidence ofeffectiveness." Many RCT studies can be done now and have sufficient preliminary data to justify controlled trials, such as many of the interventions cited in this volume. Many questions can and should be addressed by RCTs. RCTs have the highest internal validity of any clinical research method. Studies that use randomization to eliminate selection bias and blinding to reduce nonspecific effects provide strong evidence, if results are significantly positive, that a well-defined medication is better than a placebo or an active control in the carefully selected population. Although the RCT is the gold standard of medical research, by now it is well accepted that RCTs cannot answer all questions. 3l In the evaluation ofalternative medicine the RCT can be entered too early, before the intervention is standardized and the right population is identified for sampling. RCTs are also expensive, such as the $4.5 million the NIH awarded in 1997 for a trial ofSt.]ohn's wort (Hypericum perforatum) for depression (n = 300). Such expenditures cannot be made for many CAM interventions. Since funding in CAM research is limited, the value ofsmall trials, open trials, case series, and case studies should be recognized. A controlled trial generally requires four times the number ofsubjects as an open trial to detect the same therapeutic difference in an outcome measure. Although the validity of the answer is less certain, several open trials can be conducted for the same expense and difficulty of one randomized trial. Because preliminary information is needed to select the best possibilities for more stringent trials, such design compromises are reasonable in early studies. Many research designs are not frequently used but provide good information in early stages of investigational programs. Single-patient studies have reached a high level of sophistication and minimize risk to subjects. 32 -34 Observational studies can track the outcomes of a number of therapies simultaneously,S and time-series studies have been developed for office practice and applied to CAM treatments. 3S When the medicine and mechanisms are not welldefined, a best-case series method, such as the one adopted by the National Cancer Institute (NCI) for novel therapies, will be useful. The investigation of remarkable cases, such as reports of retroconversion to seronegativity, may provide excellent leads for

CHAPTER 1 Research Issues in CAM and HIV/ AIDS

follow-up.36 Case controls on hardy patients may indicate beneficial health characteristics and behaviors. 20 Open trials are valuable in AIDS research, which has hard objective endpoints such as viral load, CD4 + lymphocyte levels, the expression of uncommon infections, and survival. The methodology of the RCT is undergoing rapid evolution to accommodate patient preferences, which is an important issue in CAM research. 37 ,38 For treatments that call for adaptation of medications, such as homeopathy, response-adaptive design theory may contribute. 39 Contrary to what many alternative practitioners believe, good research designs are available even for nonmaterial interventions. 3 Of course, funding review committees need to be as open to the possibilities of alternative trial designs as CAM researchers. The many clinical cases under everyday CAM treatment are not evaluated in a consistent way. The high use ofCAM for the treatment ofAIDS is a great opportunity for community-based observational studies that scan users for associated benefits. s These indicators can then be tested further in clinical trials. Such studies are also valuable for scanning for possible harm, thus providing a great deal of information about a wide research field before turning to controlled (and expensive) randomized trials. Although the debate in conventional medicine argues over whether to allow or encourage patient access to CAM, ethics are local and should address the context in which they are applied. 40 Thus ethical issues are reduced in complexity. Similarly, regulatory issues in observational screening studies are also much reduced. The World Health Organization (WHO) (1948) defined health as a "state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity, maximizing patients' mental, physical, and social functioning."41 The two most frequently operationalized parts of this definition of whole health are (1) a sense ofwell-being and (2) functionality. The emphasis on performance distinguishes functional status from other aspects of health-related QOL. A number of validated instruments for assessing sense of well-being now exist, such as the Quality of Well-Being Scale (QWB), the Symptom Distress Scale, and the Present State Examination. Instruments assessing functionality include the Karnofsky Performance Scale, the Sickness Impact Profile (SIP), the Instrumental ADL (IADL), Neurobehavioral Function: An ADL Rating Scale, the Katz Index of Activities of

27

Daily Living, and the Functional Independence Measure (FIM). More sophisticated instruments attempt to address both the functioning and well-being dimensions of health simultaneously, most notably the several manifestations of the Medical Outcomes Survey-Short Form (MOS-SF 30, 36, 38, and 56), the Dartmouth COOP Functional Health Assessment Charts, Health Status Measures for Adults, and the QOL Instrument. Spiritual outcomes, or the individual's sense offitness in the universe and his or her personal interface with the grand mysteries of being, are less studied than other spiritual clinical correlates. A review of the literature on spirituality demonstrates the use of only one scale used to measure Spiritual Well-Being (SWB). Ellison and Paloutzian (1982) designed the SWB scale, which consists of 20 items designed to measure religious well-being (RWB) and existential well-being (EWB). More physical measures require further research as well. For example, instrumentation needs further development to measure whole-body responses to subtle influences, such as changes in low energy emissions from the body in response to Qigong. 42 Although the concentration here is on clinical work, all domains of medical research-basic science, clinical and epidemiological studies, and appropriate animal studies-have their respective strengths and should be pursued.

Test by Methods That Do Not Distort CAM Practice Most health research is oriented to products, patents, and profits. The FDA system of drug regulation was developed to both restrain and encourage the pharmaceutical industry in its current economic environment. It works quite well for molecular medical approaches with novel molecules but not for many CAMs because of the issues previously cited. Pharmaceutical firms now fund 2.5 times as much clinical research as the NIH, and both sources of research funds are devoted essentially to products or devices. Researchers have relatively little interest in CAM procedures or combination treatments, and virtually no research exists in CAM systems such as Ayurveda and naturopathy. The current environment does not encourage medical advances that are not economically protected. After doing the necessary descriptive research on CAMs, research methods should be chosen that least interfere with the CAM practices to be

28

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

studied instead of distorting CAM practices to fit models of research intended for patentable drugs. The medicine needs to be delivered in context, and broad measures ofhealth and well-being are required to evaluate its outcomes. For some studies in individualized medicines, treatment could be determined by algorithm, but for others, using expert CAM practitioners for the more complex multimodality treatments may be a necessity. The practitioner could be considered as the intervention for a trial ofa medical system. A Delphi panel of CAM practitioners could select a common treatment for a selected population sample. All of the methodologies that are appropriate to the evaluation of CAM practices have not yet been developed. Innovative designs, which CAM practitioners assert do not distort practice, will be needed instead ofconventional designs, which produce high-validity answers to the wrong questions.

Reduce the Obstacles to More CAM Research CAM clinician-scientists who have the incentive and ability to perform research studies are rare at present. The pool of researchers educated in both CAM and research methods needs to be increased, and CAM practitioners should be targeted for research traineeships. To develop CAM research infrastructure, the funding share for CAM needs to be increased, something which is occurring in the United States as the NIH National Center for CAM garners increased attention from Congress. The development of research capacity funded at CAM academic institutions is especially valuable because future research in these institutions will stay focused on CAMs rather than be diverted to more lucrative conventional drugs. Regulation is somewhat ofa deterrent to small trials. The FDA requires an investigational new drug (IND) application if a disease endpoint is being studied and toxicity data even in cases with a long history of human use. An intermediate standard for proceeding with a trial in a historical remedy for which no drug indication or regulatory protection is being sought should be explicitly implemented by the FDA. The biases that continue to pervade the current research establishment43 need to be further ameliorated. A temporary affirmative action program may be needed to appoint practitioners and researchers who

are deeply familiar with CAMs to funding and publication review panels. Every research study, especially a clinical one, is a network of compromises. The compromises relevant to the issues raised in this chapter may seem arbitrary to those who are unfamiliar with CAM. Those compromises needed to protect the integrity of the medicine being tested should be defended, as well as those made to meet other needs in a particular study. To choose where to invest research dollars, consider the traditional CAM literature, academic centers, and experienced practitioners, as well as the much more common in vitro screens of traditional (not conventional) medicines.

Persistence Is Required Finally, patience is in order. This is not easy to hear during the AIDS crisis. The CAM field is broader than the current field of conventional medicine and simultaneously holds multiple worldviews. Important questions will not be answered overnight. To realistically appraise the possibilities ofCAM, social, scientific, and intellectual changes need to be made to the structure of research activities. A CAM research system created and disappearing overnight in response to politics, marketing, or clinical fads would be particularly destructive. There is good reason to continuously dedicate a portion of the social allocation of scientific resources to exploring alternative medicine. CAM may prove to be a valuable partner with conventional allopathic, reductionistic, and molecular approaches to health care. The fundamental intentions ofallopathic medicine will be enhanced by alternative perspectives in the human response to health threats.

References 1. Spencer]W: Essential issues in complementary/alternative medicine. In Spencer JW, Jacobs JJ, editors: Complementary/alternative medicine: an evidence-based approach, St Louis, 1999, Mosby. 2. PommierJP, Gauthier L, LivartowskiJ, et a1: Immunosenescence in HIV pathogenesis, Virology 231(1): 148·154, 1997. 3. Vickers A: Methodological issues in complementary and alternative medicine research: a personal reflection on 10 years of debate in the United Kingdom,] Altern Complement Med 2(4):515-524, 1996.

CHAPTER 1 Research Issues in CAM and HIV/ AIDS

4. Calabrese C, Wenner C: Treatment of HIV-positive patients with complementary and alternative medicine: a survey ofpractitioners,] Altern Complement Med 4(3):281287,1998. 5. Standish L], Calabrese C, Reeves C, et al: A scientific plan for the evaluation ofalternative medicine in the treatment ofHIV/AIDS, Altern Tber Health Med 3(2):58-67, 1997. 6. Rosa L, Rosa E, Sarner L, et al: A close look at therapeutic touch,jAMA 279:1005-1010,1998. 7. Ernst E: Regulating complementary medicine: only 0.08% of funding for research in NHS goes to complementary medicine, BMJ 313(7061):882, 1996 (letter). 8. Gatterman MI: A patient-centered paradigm: a model for chiropractic education and research,J Altern Complement Med 1(4):371-386,1995. 9. Parsons CD, Grubb IR: Tensions between the science and ethics of HIV clinical drug trials: social constructions of the trial, Int Con!AIDS 11(1):238 (abstract no. Tu.B.523), 1996. 10. Kemper K], Cassileth B, Ferris T: Holistic pediatrics: a research agenda, Pediatrics 103:902-909, 1999. 11. Anonymous: Defining and describing complementary and alternative medicine, Panel on definition and description, CAM Research Methodology Conference, April 1995, Altern Ther Health Med (2):49-57, 1997. 12. Zaslawski C, Rogers C, Garvey M, et al: Strategies to maintain the credibiliry of sham acupuncture used as a control treatment in clinical trials,J Altern Complement Med 3(3):257-266, 1997. 13. Swanson CS: A spirit-focused conceptual model of nursing for the advanced practice nurse, Issues Compr Pediatr Nurs 18(4):267-275, 1995. 14. Roberts KT, Whall A: Serenity as a goal for nursing practice, Image J Nurs Sch 28(4):359-364, 1996. 15. Goddard NC: "Spirituality as integrative energy": a philosophical analysis as requisite precursor to holistic nursing practice,] Adv Nurs 22(4):808-815, 1995. 16. Dyson], Cobb M, Forman 0: The meaning of spirituality: a Iiterature review,] Adv Nurs 26 (6): 1183-1188, 1997. 17. Pehler SR: Children's spiritual response: validation of the nursing diagnosis spiritual distress, Nurs Diagn 8(2):55-66, 1997. 18. Turner RP, LukoffD, Barnhouse RT, et al: Religious or spiritual problem: a culturally sensitive diagnostic category in the DSM-IV, J Nerv Ment Dis 183(7):435-444, 1995. 19. Peri TA: Promoting spirituality in persons with acquired immunodeficiency syndrome: a nursing intervention, Holist Nurs Praet 10(1):68-76,1995. 20. Carson VB: Prayer, meditation, exercise, and special diets: behaviors of the hardy person with HIV/ AIDS,] Assoc Nurses AIDS Care, 4(3):18-28, 1993. 21. Hodges RD, Scofield AM: Is spiritual healing a valid and effective therapy?J R Soc Med 88(4):203-207,1995.

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22. Guillory]A, Sowell R, Moneyham L, et al: An exploration of the meaning and use of spiritualiry among women with HIV/ AIDS, Altern Tber Health Med 3(5):5560,1997. 23. Targ E: Evaluating distant healing: a research review, Altern Tber Health Med 3(6):74-78, 1997. 24. Bihari B: ]ohrei in the treatment of HIV/ AIDS, Int Con! AIDS 10(2):65 (abstract no. 537B), 1994. 25. Krippner S: A cross-cultural comparison of four healing models, Altern Tber Health Med 1(1):21-29, 1995. 26. Elbaz G: Holism: the other voice of AIDS activism, Int Con!AIDS 10(1):396 (abstract no. PDOI93), 1994. 27. Benor 0]: Healing research: holistic energy medicine and spirituality, Munich, 1993, Helix Verlag GmbH. 28. Schlitz M, Braud W: Distant intentionality and healing: assessing the evidence, Altern Tber Health Med 3(6):62-73, 1997. 29. Wirth DP: The significance of belief and expectancy within the spiritual healing encounter, Soc Sci Med 41(2):249-260, 1995. 30. Stewart MA: Effective physician-patient communication and health outcomes: a review, CMAJ 152(9): 1423-1433, 1995. 31. Rabeneck L, Viscoli CM, Horwitz Rl: Problems in the conduct and analysis of randomized clinical trials: are we getting the right answers to the wrong questions? Arch Intern Med 152(3):507-512, 1992. 32. Kiene H, von Schon-Angerer T: Single-case causality assessment as a basis for clinical judgment, Altern Ther Health Med 4(1):41-47, 1998. 33. Barlow DH, Blanchard EB, Hayes SC, et al: Single-case designs and clinical biofeedback experimentation, Biofeedback SelfRegul2(3):221-239, 1977. 34. Guyatt GH, Keller JL, Jaeschke R, et al: The n-of-l randomized controlled trial: clinical usefulness, our three-year experience, Ann Intern Med 112(4):293-299, 1990. 35. KeatingJCJr, Giljum K, MenkeJM, et al: Toward an experimental chiropractic: time-series designs,] Manipulative PhysiolTber8(4):229-238, 1985. 36. Weibo L, Ruixing W, Chongfen G, et al: A report on 8 seronegative converted HIV/AIDS patients with traditional Chinese medicine, Chin MedJ 108(8):634-637, 1995. 37. FeineJS, Awad MA, LundJP: The impact of patient preference on the design and interpretation ofclinical trials, Community Dent Oral Epidemiol26(1):70-74, 1998. 38. Rucker G: A two-stage trial design for testing treatment, self-selection and treatment preference effects, Stat Med 8(4):477-485, 1989. 39. Rosenberger WF, Lachin ]M: The use of responseadaptive designs in clinical trials, Control Clin Trials 14(6):471-484, 1993.

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40. Christakis NA: Ethics are local: engaging cross-cultural variation in the ethics for clinical research, Soc Sci Med 35(9):1079-1091, 1992. 41. World Health Organization, Regional Office for the Western Pacific: Research guidelines for evaluating the safety and efficacy of herbal medicines, Bangkok, 1993, WHO.

42. Godik EE, Gulyaev YV: Functional imaging of the human body: dynamic mapping of physical EM fields signals a breakthrough in medical diagnostics, IEEE Eng Med Bioi Mag Dec 21-29, 1991. 43. Resch KI, Ernst E, Garrow]: A randomized controlled study of reviewer bias against an unconventional therapy,] R Soc Med 93:164-167,2000.

Etiologyand Pathogenesis of AIDS ROBERT

S. ROOT-BERNSTEIN

STEPHEN J.

MERRILL

INTRODUCTION Science progresses through the constant interplay between theory and experience, which may occur in several ways. One employs a recursive process, in which a researcher creates a theory to explain a set ofobservations; makes predictions and tests them through further observation; modifies the theory in light of any new data; and makes new predictions. Two problems with this method are (1) that progress is incremental and (2) fundamental assumptions are infrequently challenged by observation. Data that support a theory are always easier to find than data that challenge it. Consequently, flaws in recursively tested theories often go unrecognized for extended periods of time. One alternative is to use a dialectical method in which a

thesis is contradicted by an antithesis with the goal of creating a new, more powerful synthesis. Unfortunately, dialectical methods are more likely to result in polarization of the issues, which leads to controversy that cannot be resolved, rather than a synthetic leap forward. A second, more workable alternative generates a wide range of tentative, competing explanations at the outset of research. Each explanation makes widely different predictions, which are used to create tests that can differentiate between their explanatory powers. The advantage of this method is that the researcher can quickly narrow down the types of theories most likely to suffice for any particular problem and simultaneously be assured that crucial assumptions underlying the different theories are tested against one another. The disadvantage is that the

31

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AIDS AND COMPLEMENTARY & AL TE RNATIV E M EDICIN E

researcher must keep an open mind and take care not to become attached to a particular explanation in advance of relevant data. All three methods are used to address acquired immune deficiency syndrome (AIDS). Mainstream researchers, comprised mainly ofvirologists, defined the standard approach to AIDS early in the epidemic when they focused on finding a new virus. Their underlying assumption was that a new disease required a new disease agent. The discovery of human immunodeficiency virus (HIV) in 1983 confirmed rheir expectations and set the course of AIDS research firmly on the track of the one disease agent/one disease/one treatment dogma that served Western medicine for nearly a century. Advances in AIDS research stemmed largely from the incremental, recursive development of the HIV theory, which states that HIV is both necessary and sufficient to account for the degeneration of the immune system as AIDS progresses. The HIV theory is the only theory to garner significant funding so far. From the outset, some researchers were not convinced that HIV had the characteristics necessary to cause AIDS. These researchers range from PapadopulosEleopulos and her colleagues, who claim that HN is an artifact ofvirological isolation methods that do not satisfy any ofthe criteria necessary for the identification of a new virus, to Nobel Prize winner Kary Mullis, who believes that HN exists but has nothing to do with AIDS.l The most notable contrarian is Peter Duesberg. Duesberg, a virologist, believes that the existence of HIV has been demonstrated formally but doubts its pathogenicity. He adopts a dialectical approach to the HN hypothesis, claiming that HN is a "pussycat" that cannot cause disease. Many of Duesberg's early criticisms were cogent and gained widespread attention, spurring some important tests of the HIV theory. His failure to pose an alternative explanation for AIDS, however, presented a stumbling block to further progress. His theory that drug use, including antiretroviral drugs such as AZT, causes AIDS has neither gained acceptance nor generated any corroborative research results to date. 2 A third group of investigators employing the multiple hypotheses approach to AIDS has also existed from the outset of the epidemic. They were led by Joseph Sonnabend, who noted even before HIV was isolated that the discovery of any new disease agent would have to be placed in the context of multiple immunosuppressive agents encountered by all

individuals who contracted HIV and developed AIDS. Sonnabend pointed out the politically unacceptable observation that gay men and intravenous (IV) drug abusers who contracted HIV were also characterized by multiple, concurrent infections from sexually transmitted diseases (STDs); chronic infecrions from viruses known to be immunosuppressive, such as herpesviruses, cytomegalovirus (CMV), and hepatitis viruses; very high rates of antisemen antibodies that cross-reacted with and killed T cells; and the use of drugs, such as heroin, morphine, cocaine, and nitrite inhalants that have immunomodulatory effects. Consequently, Sonnabend argued that HIV might play any of several roles in AIDS: (1) it might be necessary and sufficient to cause AIDS; (2) it might be necessary but not sufficient; or (3) it might be an opportunistic infection (01) taking advantage of an already compromised immune system. 3 -5 We follow Sonnabend's lead by adopting the multiple hypotheses method. 6 -8 Consequently, we focus on the predictions that allow one theory to be distinguished from another and the phenomena that one would expect to observe, depending on which theory is correct. We also summarize the data that have been accumulated by an evergrowing number ofinvestigators suggesting that there is more to AIDS than HIV.

ALTERNATIVE THEORIES Standard textbook accounts ofAIDS pathogenesis describe a process in which HIV infects CD4 + T lymphocytes (hereafter referred to as T cells), macrophages, and dendritic cells, creating a persistent, low-level infection that slowly wears down the immune system over time. The exact mechanisms of cellular death are still the subject ofintense investigation that includes possibilities such as HN-triggered apoptosis (programmed cell death), direct cellular killing, and indirect cellular killing due to observed increases in cytokines, tumor necrosis factor (TNF), and related molecules. 9 ,10 Some investigators note that HIV proteins have significant homologies to human proteins, including class II major histocompatibility complex (MHC II) proteins and that most people with AIDS develop autoantibodies against T-cell determinants. These observations led to the hypothesis that HN may trigger an autoimmune process in which B cells produce antibodies against HIV that cross-react with and

CHAPTER 2 Etiology and Pathogenesis of AIDS

kill T cells. I I· IS Other investigators note that HN proteins have significant homologies with various nerve toxins, suggesting that the dementias associated with HIV infection may result from the buildup of toxic protein fragments from HN.16 The key implications of the theory that HN is both necessary and sufficient to cause AIDS (hereafter, the HN-only theory) are as follows: (1) we are all at equal risk ofHN infection and AIDS, (2) everyone exposed to an equal dose of HN should have an equal chance of chronic infection, (3) everyone infected with HIV should (within probabalistic variability) progress to AIDS at the same rate as everyone else, and (4) the only way to stop the progress ofAIDS is to stop HN.9,10 The second theory we consider is the cofactor theory, which has two major versions. The first version of cofactor theory retains the basic premises of the HIVonly theory and adds the prediction that the rate of AIDS development after HN infection is determined by the presence or absence of specific cofactors. HIV infection requires that a potential T-cell host be in an activated or stimulated state,17 and HN replication requires that the infected T cell be stimulated. '8 ,19 Although HN-only theories suggest that HN creates its own stimulated lymphocytes, many investigators believe that the necessary activation can be achieved by other factors. These cofactors may be other viral, bacterial, or parasitic infections, as well as exposure to allogeneic antigens such as those found in blood and semen. 4,6,7 Broadening the definition of cofactors to include any factors or conditions that can change the natural history of HIV infection expands the cofactor list to include immunosuppressive drugs, malnutrition, or anything else that has a profound effect on immune function. 6,7 Thus this type ofcofactor theory suggests that individuals with different post-HIVinfection risks have different natural histories of infection and as a result progress to AIDS at different rates. Conversely, the treatment ofcofactor infections and conditions has a pronounced effect on development ofAIDS. We call this the cofactor-promoted HN theory. A second version of cofactor theory argues that HIV is necessary but not sufficient to cause AIDS. Those who favor this approach to understanding AIDS argue that in the absence of cofactor exposures, HN is neither able to infect people nor able to replicate within individuals once infection has occurred. This cofactor theory also posits that the cofactors play an essential role in establishing the immune status

33

and susceptibility to HIV before exposure. Thus healthy individuals are unlikely to become infected with HN, and HN-infected individuals who can eliminate existing cofactor risks and avoid future ones may be able to drive their HIV infection into latency. In contrast to the cofactor-promoted HN theory, the risk of infection is determined by cofactor exposure. Both theories postulate that the rate of progress to AIDS after HN infection is determined by cofactor presence, but since cofactors are necessary and not just modulatory, elimination of cofactors should be as effective at stopping AIDS as is treatment ofHN.4,6,7 We call this the cofactors-required HN theory. A final theory should also be considered both to cover all the possibilities and to establish the null hypothesis. We must consider the possibility that HIV is neither necessary nor sufficient to cause AIDS. In this case two different explanations of AIDS are possible. First, HIV may be one of many immunosuppressive agents present in people who develop AIDS, having no greater or lesser bearing on pathogenesis than any of the others. Second, HIV is simply another 01 typical ofsignificant immune dysfunction but is actually secondary to the causes of AIDS. The implications are that AIDS is either the result of a single causative agent that has not yet been discovered or a multifactorial disease caused by an accumulation of immunological insults over time. In the second case it should be possible to demonstrate that people at risk for AIDS develop severe immune suppression either before exposure to HIV or in its complete absence. A significant number of people who have developed AIDS without being infected by HIV should exist, and the nature of the immunosuppressive risks encountered by these individuals should provide strong clues to the true causes of AIDS. 1,2 Thus treatment of HIV would be of secondary importance in preventing AIDS. We call this the non-HN theory. One caveat is in order when considering cofactor and non-HIV theories. A significant difference exists between the symbiotic interactions of disease agents, synergistic interactions, and progressive accumulation theories. In a symbiotic interaction, both agents are necessary for functionality. For example, Shope discovered in 1931 that swine flu in pigs is caused by a combination of a virus and a bacterium, neither of which is pathogenic in pigs by itself. 20 This case is quite different from that observed in the synergism between alcohol and barbiturates. Alcohol and barbiturates are each capable of causing death in large quantities but

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can cause death when taken together in relatively small amounts. Their effects are more than additive. Synergism in tum must be contrasted with progressive accumulation of exposures to immunosuppressive agents, in which the effects would be purely additive. According to a cumulative exposures or an antigenic overload theory of AIDS, immune destruction is the simple result ofimmunological depletion. 4,s,21.24 Thus we must consider the possibility that the dose of HIV and the dose of any putative cofactors are critical factors in determining the outcome of infection. Large doses of HIV may not require cofactors, but cofactors may greatly potentiate HIV activity or even cause infection with otherwise noninfective doses of HIV (an effect compatible with either a cumulative exposures theory or a synergistic theory). On the other hand, HIV may require cofactors (a symbiotic theory) along the lines of Shope's swine flu model in pigs. Synergistic theories also do not eliminate the logical possibility that a sufficient dose of cofactors might be capable of inducing acquired immunosuppression, just as alcohol or barbiturates are, in large enough doses, each capable ofinducing death. The point is that not all alternative theories ofAIDS are mutually exclusive, and therefore no single set of data will suffice to differentiate one theory from another.

CRITICAL STUDIES DIFFERENTIATING THE THEORIES The critical information required to differentiate one theory from another can be summarized into the following categories: (1) tests of the null hypothesis (i.e., what evidence exists for AIDS without HIV?); (2) data concerning average rates of progression of different risk groups from HIV infection to AIDS; (3) clinical and epidemiological studies of the influence of specific cofactors on the progression ofHIV infection; (4) laboratory studies of the influence ofcofactors on HIV activity in vitro; (5) data concerning risk ofHIV infection that depends on the nature of the exposure or health status at time ofexposure to HIV; and (6) studies of the effect of treatment of cofactor risks on progression to AIDS. First, we must test the null hypothesis by determining whether HIV is necessary to cause AIDS. The standard approach to this question is to point to large-scale clinical studies of people in high-risk

groups for AIDS, such as gay men and hemophiliacs, that compare the incidence of AIDS in the presence and absence of HIV. All such studies unanimously conclude that HIV is necessary to cause AIDS because people without HIV infections have never developed severe immunosuppression or AIDS in any of these studies. 9 ,lo,2s The only reason that the issue can reasonably be raised at present is that a very small number (much less than 1% of AIDS cases even by Duesberg's2 most optimistic count) of idiopathic cases resembling AIDS in individuals with no evidence of HIV infection continuously tum up. Most of these cases are subsumed under the rubric of idiopathic CD4+ T-cell lymphopenia (ICL), in which helper T-cell counts drop below 300 and OIs, Kaposi's sarcoma (KS), or central nervous system (CNS) lymphoma ensues. 26 ,27 Unfortunately, the meaning of these cases is open to several interpretations. One is that as yet unidentified causes of immune suppression much rarer than HIV exist. According to this interpretation, HIV is the cause ofAIDS, and exceptional cases have exceptional causes. Studies of hospitalized patients, blood donors, and HIV-negative people in West Africa all suggest that ICL is indeed an exceptional syndrome. 28.3o ICL has, however, been found to occur at significantly higher rates among sexual partners ofHIV-infected individuals and others at risk for AIDS than among the general population. 31 These results suggest two additional interpretations. One is that these idiopathic cases disprove the HIV theory. Duesberg and his colleagues 1,2 interpret all cases of ICL to support the thesis that HIV does not cause AIDS. The HIV theory, however, cannot be disproved by the simple observation of exceptions. Idiopathic versions exist for virtually every disease, Acquired immunosuppression may have several causes, HIV being only one of the most common. Evidence that some forms of acquired immunosuppression occur in the absence of HIV does not invalidate the HIV-only theory any more than the evidence that pneumonia can be caused by Pneumocystis carinii disproves the theory that pneumonia can also be caused by Mycoplasma pneumoniae. An additional step is necessary: to demonstrate that AIDS is caused by some agent or agents that are present not only in people infected with HIV but also in those with idiopathic immunosuppression. This second step has not been carried out successfully at present. The fact that lymphopenia occurs much more frequently among those at risk for AIDS than among the

CHAPTER 2 Etiology and Pathogenesis of AIDS

general population suggests yet a third possibility, which is that HIV is the primary cause of AIDS but that cofactors associated with immunosuppression in AIDS may, in rare circumstances, synergize to create an AIDS-like symptom in the absence ofHIV. In this case significant immunosuppression should be evident in some individuals exposed to putative AIDS cofactors in the absence of HIV infection. This is in fact the case for many people at risk for HIV, although the resulting immunosuppression is rarely sufficiently severe to result in OIs.6,7 These cofactors may increase susceptibility to HIV and, under unusual circumstances, progress to AIDS independent of HIV. However, we will proceed on the basis that HIV is necessary to cause AIDS because all existing data are currently consistent with that proposition. We will concentrate instead on the question of whether HIV is sufficient. Data concerning the rate of progression to AIDS after HIV infection can help to differentiate the HIVonly theory from cofactor theories. Different risk groups have widely different exposure rates to infectious and STDs, antibiotic use, immunomodulatory drugs, malnutrition, allogeneic stimuli such as semen or blood products, and preexisting medical impairments. 6,7 If cofactors affect progression from HIV infection to AIDS, then these different exposures should translate into observable rate differences. However, if HIV is both necessary and sufficient to account for AIDS, then no risk-group difference should be apparent. Weiss 9 has in fact claimed that people in all risk groups do progress to AIDS at the same rate (an average of 10 years from HIV infection to AIDS). The one exception that Weiss admits is young hemophiliacs, who survive somewhat longer (and whom he conjectures may start with higher numbers of T cells than older individuals have). Weiss concludes that cofactors play an insignificant role in AIDS pathogenesis. Root-Bernstein,32 however, performed a more extensive study of available data and found, contrary to Weiss, that significant differences exist between rates of progression in risk groups. The rate of progression among young hemophiliacs is even slower than Weiss reported, averaging more than 20 years. Transfusion patients, whose date of infection is known, progress significantly faster than gay men or older hemophiliacs (averaging about 6 years from HIV infection to AIDS). People who contract HIV during a transplant operation and are subsequently immunosuppressed for thera-

35

peutic reasons develop AIDS on average within 2~ years,33 and infants infected with HIV either serorevert or develop AIDS on average within 6 months. (Figure 2_1)32 Additional studies confirm that rates of progression to AIDS differ by risk group.34.38 Notably, elderly individuals (over the age of 60) have an increased rate of progression to AIDS compared with other population groups.39 Thus little doubt exists that cofactors play some role in AIDS pathogenesis. Clinical and epidemiological studies ofAIDS progression give a more precise picture of AIDS pathogenesis that also suggests pivotal roles for cofactors. Once again, if HIV were responsible for all aspects of immune pathology in AIDS, then the presence or absence of other immunomodulatory diseases or agents would be expected to be irrelevant to AIDS progression, but this is not the case. Immune stimulation providing a broad source ofactivated macrophages and T cells is now generally considered to be a dominant feature ofAIDS pathogenesis. 35 ,40.42 In addition, T-cell activation is shown to be a more important indicator of shorter survival than is HIV plasma burden or virus chemokine receptor usage (viral tropism).43 A wide range of infectious agents are also known to infect T cells and macrophages, causing immunosuppression independent of HIV. These include CMV, hepatitis viruses (HBV and HCV), human T-Iymphotropic viruses (HTLVs) types I and II, human herpesvirus (HSV, HHV-2, or HHV-6), and mycoplasmas. All of these infectious agents are highly associated with and actively produced and excreted by people infected with HIV. There is no reason to think that their immunosuppressive activity is eliminated simply because HIV is present, and there is every reason to believe that activation of these agents results in increased immunosuppression. The agents identified as cofactors of HIV infection, either through stimulation or suppression, are presented in Table 2-1. Evidence showing increased rates of progression from HIV infection to AIDS associated with particular cofactors is widespread. CMV clearly speeds the rate at which HIV progresses to AIDS,44,45 activates HIV-l expression in coinfected chimpanzees,46 and encodes a chemokine receptor used by HIV as a cofactor for lymphocyte entry. Other herpesviruses encode similar receptors. 47 Other infections commonly associated with AIDS that also increase disease progression include HHV_6,48,49 HTLV-II,50,51 hepatitis viruses,52,53 tuberculosis,54,41 febrile episodes of herpes zoster (HZ),55 and malaria.56

36

AIDS AND COMPLEMENTARY & AL TE RN ATIVE MEDICINE

100"'F=-:O::::::::~-==\.4C==:-----I;r-----v-----v

80

en 60 0

« '5

0 .t:

j

c:

~

Ql

Q.

40

20

O+---r---r--...,.--.,----,---r-----.--,----,

o

2

3

4

5

6

7

8

9

Years

\1 HIV-negative men and hemophiliacs (Weiss)9 • HIV-positive hemophiliacs under age 25 (Root-Bernstein)32

o HIV-positive hemophiliacs under age 25 (Weiss)9

T

HIV-positive blood transfusion patients (Root-Bernstein)32

+

HIV-positive transplant patients (Root-Bernstein)32

•

HIV-positive pediatric patients (Root-Bernstein)32

D HIV-positive hemophiliacs over age 25 (Weiss)9 Figure 2-1 Proportion of individuals surviving without AIDS plotted with data combined from various European and North American studies. (See Root-Bernstein 32 for details of all studies.) Note that no study of HIV-positive transplant patients larger than 2S patients was performed so that statistical variation in reported AIDS-free survival times varies much more widely than in studies of other risk groups. To indicate variation, bars were added to the transplant patient points to indicate the range of reported data, and the points themselves were drawn from a large study of 22 patients by Lang et ai, 1991. Note the tailing off of AIDS risk with increasing length of AIDS-free time in infants and transplant patients.

CHAPTER 2 Etiology and Pathogenesis of AIDS

37

TABLE 2-1

Identified and Potential HW Cofactors Agent

Viruses Adenoviruses Influenza Cytomegalovirus Epstei n- Barr Hepatitis C Herpes simplex-' Herpes simplex-2 Herpes simplex-6 Human foamy virus HTLV-' Varicella-zoster

In vivo evidence

In vitro evidence

x x x x x x x

x x

x x x x

x

Bacteria Gardnerella vaginalis M. avium complex M. tuberculosis Mycoplasmas T. pal/idum (Syphilis) Mastitis

x x x x x

Protozoa P. carinii Giardia lamblia (Giardiasis) P. falciparum (Malaria)

x x x

Agent

Vaccines Influenza Pneumococcal Tetanus toxoid Drugs Opiates Cocaine Inhalant nitrites

I" vivo evidence

In vitro evidence

x x x

x

x

x

x

x

Immunological Alloantigens Blood transfusions Clotting factors Semen

x

Malnutrition

x

x

x x

x

x

x

Adapted from Root-Bernstein, 1992, Wahl, Orenstein, 1997; Cytomegalovirus from Kovacs et ai, 1999, Perez et ai, 1998; Herpes simplex-2 from Perez et ai, 1998; Herpes simplex-6 from Emery et ai, 1999; Human foamy virus from Marino et ai, 1995; Varicella-zoster from Alliegro et ai, 1996; G. vagina/is from Hashemi et ai, 1999; Mycoplasmas from AI-Hathi et ai, 1999, Grau et ai, 1998, Perez et ai, 1998; T. pallidum (in vivo) from Otten et ai, 1994, Kourmans et ai, 2000; T. pal/idum (in vitro) from Theus et ai, 1998; Mastitis from Semba et ai, 1999; P. fa/ciparum (in vitro) from Hoffman et ai, 1999; P. fa/ciparum (in vitro) from Xiao et ai, 1998; Opiates and Cocaine from Gorenbladh, Gunue, 1989, Weber, 1990; Alloantigens from Root-Bernstein, 1993, Root-Bernstein, DeWitt, 1995; Malnutrition from Chlebowski et ai, 1995, Coursoudis et ai, 1995.

Some infections alter the probability of primary HIV infection. The most clear-cut examples are STDs that result in open sores, thereby promoting HIV entry

the blood and immune systems and simultaneously producing immune system activation. 57 People actively excreting Epstein-Barr virus (EBV) in urine or saliva are more likely to seroconvert than those with latent infections or who have never been infected.58' 60 EBV also allows HIV to infect B cells, a process that further destroys immune function. 61 . 63 Both chlamydia infections 64 and helminths 65 also increase the probability of acquiring HIV. to

A significant number ofstudies have failed to find any cofactor effect of some of these agents. All of the negative studies suffer, however, from having examined antibody prevalence rather than active infection. Since nearly every person at risk for AIDS has been exposed to CMV, EBV, and herpesviruses 7 and probably carries them latently, antibody prevalence is intrinsically unable to statistically distinguish between those at risk for AIDS and those with AIDS, or between those progressing quickly with AIDS and those progressing slowly. We do not therefore consider antibody prevalence studies to be useful in this context. To

38

AI DS AND COMPLEMENTARY & AL TE RNATIVE MEDICINE

determine whether an infectious agent is promoting HIV activity requires measurement of that agent's production or excretion. Most studies of the effect of active infection with a cofactor on the rate of progression to AIDS show significant effects. In addition, if the cumulative effect of many agents involved in active infection is most significant in altering the progression rate, demonstrating that anyone agent significantly causes this effect may be difficult. Laboratory studies also implicate an important role for cofactors in AIDS pathogenesis. As noted, HN requires activated T cells to infect and replicate, and elaborate schemes were devised by some AIDS researchers to explain how HN could act as a selfstimulating infection, but laboratory evidence shows that HN rapidly becomes latent or disappears altogether when T cells from a healthy individual are exposed to it. Laboratory models ofHN infection employ either specially susceptible leukemia cells or cells stimulated with viruses, mitogenic agents, or various drugs.!s.66.67 Not only can we assume that similar requirements are present in living human beings, but evidence exists that many people exposed to HN do in fact eliminate their infection without producing antibodies. 68' 7o Laboratory studies show that the same agents that increase the rate of progression to AIDS also have a significant effect on HN infectivity, replication, and pathogenicity in vitro. Both influenza3 ! and tetanus toxoid7! inoculations markedly increase HN replication and serum levels of HN in infected individuals, and tetanus toxoid has the same effect in vitro'?! These results clearly show that when T cells are activated, HIV replication and infectivity increase. Thus any agent that stimulates T-cell activity can be expected to stimulate HIV activity as well, a critical observation that must be considered in the development of any new AIDS therapy. In addition to T-cell stimulation being directly responsible for the modulation of HN replication, the infective ability of that virus is partially controlled by chemokine receptors. These receptors are cofactors for HN infection ofa susceptible cell and are modulated by the stimulatory agents identified earlier. The role of these receptors in the process of HN infection is reviewed in Fauci25 and Cohen et al. 72 One final type of immunological factor-autoimmune processes-must also be considered, since it can both stimulate T cells and cause immune suppression by means of direct cell killing. People with AIDS have been known to develop a large number ofdifferent autoimmune diseases and at rates that are often hun-

dreds of times higher than that of the general population. These diseases range from arthritis and demyelinating processes to autoimmune liver and kidney disease, as well as Sjogren's syndrome. 6.73 Perhaps most confounding is the observation that most people with AIDS develop autoantibodies directed against their own T cells and that in most cases these autoantibodies are cross-reactive with autologous antigens such as semen.?4 Most hemophiliacs who develop AIDS also develop very high levels of anti-B-cell autoantibodies. Thus it is not incorrect to characterize a significant portion of AIDS pathology as resulting from an autoimmune process against the immune system itself. What role this autoimmune process plays in providing an appropriate niche for HIV within the immune network has yet to be determined. It is not known what triggers these autoimmune phenomena. Some investigators believe that HIV is at fault, since HIV has proteins that mimic MHC-II proteins. ll '!6 Other researchers have evidence that the autoimmunity may result from repeated exposure to alloantigens, such as sperm, semen, leukocytes, or blood. 74' sO Others suggest that autoimmunity results when the immune system is overwhelmed by specific combinations ofagents. 6,7,74 Three experiments are particularly notable. The first was performed by Kion and Hoffmann,S! who showed that mice who develop a spontaneous lupuslike disease also develop an antibody repertoire typical of HIV-positivity-without ever having been exposed to HIV. StottS2 reported similar findings in HIV-negative macaques. More recently, Ter-Grigorov et al s3 created a new model of AIDS in mice by inoculating them with large doses of paternallymphocytes. The mice develop dramatic depletions ofCD4+ cells, progressive impairment of immune responses, and Kaposi's-like sarcomas or terminal B-celilymphomas-in the absence of any known retroviral exposure. The researchers have not ruled out the possibility that an endogenous retrovirus is activated by their experimental procedure; however, since the disease is transmissible by serum from one animal to another. Much of what we have taken to be evidence of immune impairment caused by progressive HIV infection may in fact be the result of non-HIV processes. HIV may be taking advantage of these other processes, thus acting as a synergistic or opportunistic rather than a strictly pathogenic agent. In addition to clinical and laboratory evidence that cofactors playa significant role in AIDS pathogenesis,

CHAPTER 2 Etiology and Pathogenesis of AIDS

studies of who is at risk for infection also suggest a role. This model may explain a number ofexceptional observations concerning HIV transmissibility. For example, it is well established that significant differences in susceptibility to HIV exist. Patients exposed to HIV via a blood transfusion seroconvert more than 60% of the time,84 whereas persons exposed to HIV via a single dose of contaminated factor concentrate seroconvert about 5% of the time. 85 Health care professionals exposed percutaneously to HIV seroconvert only 0.3% of the time. 86 Although part of the difference in transmission may be due to HIV dose, another major difference between people in high-risk groups and the typical health care professional is that rates of putative cofactors for HIV are hundreds to thousands of times higher among the at-risk groups? Interactions between HIV and cofactors have an important implication. Because HIV requires activated lymphocytes to infect and replicate and because many of the cofactor infections just described also use lymphocytes to infect and replicate, AIDS progression should be manifested not only by increased HIV viremia but also by increased cofactor viremia. In essence, a vicious cycle should be initiated in which each virus primes further activity of the other. This is in fact the case. EBV and CMV viremia are both accurate markers for disease progression. 87-93 Measures ofautoimmune processes such as circulating immune complexes and lymphocytotoxic antibodies have also been found to accurately predict AIDS progression. 5,68,94-99 Notably, both viral infections and autoimmune processes result in release of interferons (IFs), interleukins (ILs), TNF, and other chemokines often mistakenly attributed solely to HIV activity.5,7,25,100 Thus any attempt to argue that HIV is the sole, necessary cause of AIDS must measure not only HIV but control for other immunologically active agents and processes. Only rarely are such controls run by those studying the role of HIV in AIDS, and thus any conclusions drawn by such uncontrolled studies must be suspect in light of the data just summarized. One final type of evidence also argues against an HIV-only theory ofAIDS pathogenesis, The treatment or elimination of putative cofactors for HIV often slows progression to AIDS significantly. Many studies suggest that elimination of ongoing risk factors that continuously reexpose individuals to HIV and its putative cofactors can slow progression to AIDS or result in rare seroreversions (i.e., loss ofHIV-positivity), Thus people

39

who stop using addictive drugs,101,102 people who stop engaging in high-risk sexual behaviors, 103·105 and hemophiliacs who are switched from impure factor concentrates to those with a high-purity factor,106-108 all experience significant improvements in clinical measures of disease progression. Nutritional changes to correct metabolic dysfunctions have also been found to improve survival and increase longevity ofpeople infected with HIV.109,110 Most importantly, many studies find that treatment of cofactor infections delays AIDS onset and progression. These include prophylaxis against mycobacteria, 111 treatment of CMV, 112-ll4 treatment of malaria,ll5 and the recently discovered anti-EBV and anti-hepatitis benefits of so-called antiretroviral drugs. ll6-ll9 The only possible conclusion that can be drawn from these laboratory and clinical studies is that AIDS pathogenesis involves more than just HIV. Therefore theories ofAIDS and treatments for AIDS must both take into account factors other than HIV if they are to be accurate and effective.

MATHEMATICAL AND STATISTICAL MODELS OF AIDS Mathematical and statistical models of AIDS can be used in addition to experimental and clinical studies to investigate and compare theories of AIDS pathogenesis. Such models are generally of two basic types: (1) models of the epidemiological behavior of the epidemic, and (2) models of the effect ofHIV and cofactors on the immune system. We consider both types. Quantitative descriptions of the AIDS epidemic beyond descriptive analysis of the data (e.g., graphs, histograms, and computations ofaverages) necessarily involve the use of mathematical and statistical models. These models are actually an assortment of assumptions and simplifications that reflect the collective understanding and disposition of the investigators concerning the natural history of the disease and how it is spread. Different researchers propose different models by necessity, as each individual brings to the problem his or her unique educational experience and worldview-a mathematician sees the problems as primarily mathematical and a virologist views the same problems as an exercise of virological methods. Difficulties with models of the AIDS epidemic come from the nature of the available data. First, there

40

AIDS AND COMPLEMENTARY & ALTERNATIVE MEDICINE

is never enough data, failing in either quality, quantity, or both. Gaps in the data record make necessary additional assumptions concerning what the data would look like if it had been collected. This process is equivalent to creating a line drawing from a "dot-todot" children's picture. If sufficient data (dots) and how these data relate to one another (the dot order) is available, then each person draws essentially the same conclusions (the line drawing). If, however, the data are too sparse or relationships between the data sets are not known, assumptions must add additional dots to the picture and specify the relationship between the new and original dots. Each different collection of new dots and numbering (assumptions) gives rise to different line drawings-all of which are consistent with the original dots. In other words, different assumptions can result in different quantitative predictions based on the same data. An illuminating discussion ofsuch differences can be seen in early computations of the mean time to AIDS (i.e., the mean of the latency or incubation time distribution). Assuming that the time to AIDS followed a commonly used distribution in reliability and survival analysis-a simplified Weibull distribution-a mean latency of 4 to 5 years was computed by examining parameter values of the distribution that gave the best fit to available data. This mean latency was widely believed to be a useful estimate. It was later shown that if a more general form of the Weibull distribution was assumed, such as a distribution that contained more parameters than the simplified one, the values of the parameters leading to the best fit to the same data set corresponded to a mean latency time of 200 years. 120 The two distributions fit that data equally well. The differences in these estimates for the mean latency indicate the difficulties in using models to fill in the gaps when the data are too sparse and the care needed in using and interpreting those estimates. Second, data are always uncertain. For instance, a long and highly variable time exists between HIV infection and discovery of an immune response to this exposure detected through an AIDS test. A highly variable period of time (the incubation time) from initial HIV infection to the clinical diagnosis ofAIDS also exists. The resulting uncertainty in quantities like the "number of infected individuals" have made many models, which may have been based on adequate assumptions, unable to successfully forecast the future size of the epidemic. Kault 121 states:

Mathematical models of the AIDS epidemic have not been able to give accurate predictions about the size ofthe epidemic because it is not possible to obtain sufficiently accurate measurements of the factors that enable HIV transmission.

Using the previous analogy, this problem corresponds to uncertainties in the position and number of the original dots. This observation dictates that not all questions can be resolved by modeling methods. The effect of such uncertainties in AIDS epidemiological data is fully discussed in DeGruttola and Lagakos. 120 Given a set of assumptions (i.e., a model) and appropriate data, estimates and predictions in the form ofgraphs and tables result. A seemingly contradictory observation is that ifa set ofassumptions gives rise to incorrect predictions (and the data uncertainty is small) at least one assumption was incorrect or the simplification was unjustified. If a forecast or prediction is confirmed (additional data dots did not invalidate the line drawing), the only conclusion is that the assumptions and simplifications are consistent with the data-but the validity of the assumptions is not directly tested. The preceding discussion shows that science progresses when a model fails (i.e., something thought to be true is not), while success of a model only demonstrates consistency of the ideas with the current data. The power ofa mathematical or statistical model is that the logical consequences of a set of assumptions are revealed. If these consequences are not confirmed by data and observations, then the assumptions must not have been correct. Thus models can be used as an important tool in the scientific process. Theories (i.e., models) are proposed and tested, resulting in new and improved theories. Unfortunately, models that fail are rarely published, so inconsistencies in assumptions and current belief (i.e., the dogma) are not always recognized. Mathematical and statistical models of the AIDS epidemic have been used to forecast the extent ofdisease spread, probe the understanding of the nature of transmission of HIV through the various transmission modes, identify significant subgroups and describe the transmission within and between these subgroups, and estimate quantities such as the incubation time in different infected groups. Several collections, reviews, and monographs of this work are available. m -130 These efforts indicate the wide range of epidemiological modeling of AIDS and technical difficulties in this type of research.

CHAPTER 2

Discoveries made on the basis of epidemiological models often show that a simpler model cannot fit the known data but adding one suspected feature to the model can. Typical examples include the discoveries that a high-risk core group is needed to fit early epidemic data,131 high risk of HIV transmission is concentrated in a relatively brief period of primary infection,131 antiviral (AV) therapy can increase the number ofAIDS cases,132 infectivity changes with time,133 and careful descriptions ofpartner formation are necessary to make accurate predictions for sexual transmission of HIV.134 Several studies exist in which the model used in the epidemiological study shed additional light on immune pathogenesis. Weyer and Eggers 135 observed that within each risk group the growth of the epidemic was initially exponential with approximately the same rate (but each was shifted in time to different starting points). They noted that the spread within any group must be independent of the nature of sexual activity or drug use-those factors determining the time at which the epidemic enters the group but not the rate ofspread within the group. Through a mathematical model, they demonstrated that if an infectious cofactor was present, this same pattern results. Without the assumption ofan infectious cofactor, different rates ofspread in the groups are predicted. HIV has stayed largely within specific high-risk groups defined at the beginning of the epidemic (e.g., gay men; IV drug abusers; people exposed to blood and blood products; and populations in which malnutrition, STDs, and parasites are endemic), demonstrating that differential rates ofHIV spread are the rule rather than the exception. Thus theory and epidemiology agree that cofactors appear to playa critical role in the transmission ofAIDS. The relationship between tuberculosis (TB) and HIV is a recent concern for health professionals, especially since HIV infection increases the number of identified cases ofTB.136 Active TB infection also increases the rate of HIV disease progression. 54 A proposed mechanism for the increased rate of immune deterioration was proposed by Placido et al,137 who showed that viable Mycoplasma tuberculosis increases rates of apoptosis of alveolar macrophages in AIDS patients. Apoptosis does not increase with HIV alone. The microenvironment in the lungs ofTB patients may also be rich in cytokines, which stimulate HIV replication.138

Etiology and Pathogenesis of AIDS

41

Hepatitis B is implicated as a cofactor in two ways. First, Twu et al53 make a case for an increased number of HIV seroconversions in active HBV-infected individuals, after controlling for sexual behavior and changes in disease over time. This suggests that either an existing active HBV is a cofactor that helps to establish HIV infection after exposure or that HBV is a surrogate for other factors that perform that function. A second form of interaction is seen in an increased disease severity in children infected with both HIV and hepatitis. 52 Similar results have been recognized with coinfection with HTLV-II.5o Striking evidence for the role of cofactors in disease progression comes from two fronts. First, Alliegro et al55 report that incidents offever associated with HZ infection are associated with an acceleration of the progression to AIDS, suggesting that the increased stimulation ofT cells associated with acute herpes episodes can increase viral replication in an existing HIV infection. Second, physicians treating malaria have noticed an increased progression of HIV in infected patients. 56 The relationship between malaria and HIV promises to be similar to that of TB and HIV.139 Mathematical models ofHIV infection are used to investigate the interaction of HIV with the immune system, the effect on the disease process of the development of diversity in the HIV genome, the effect of drug treatments, and the role ofstimulatory cofactors. These studies tend to be more theoretical in nature than the epidemiological modeling, since that work is motivated by collected data. Equivalently detailed data concerning HIV infection within individuals are not generally available. A difficulty with using mathematical models as tools to study disease mechanisms is that to obtain results from a model, a larger number of assumptions and simplifications must be advanced. Many of these assumptions and simplifications are technical (and usually ad hoc), such as "the blood is a wellmixed medium," whereas others deal specifically with aspects of the theories being tested. Since the output of a model depends on the collection of all assumptions and simplifications made, including the technical ones, a direct and unambiguous comparison of theoretical alternatives is not possible. This difficulty is not unfamiliar to medical researchets, since in vivo experiments involving animal models must deal with the applicability to humans.

42

AIDS AND COMPLEMENTARY & ALTERN ATIVE MEDICINE

They must answer the question, "Does the result depend on the species chosen?" In a sense, though, the models have been successful in their failures. Data that appear after the model has been published sometimes point out that the collection of assumptions on which the model is based was incorrect. For instance, all of the early models of the interaction ofHN with the immune system (about 20 of them) used standard assumptions about disease progression taken from other theories of epidemics and immunology and predicted that kinetics for CD4 T-cell counts would either drop quickly to zero (usually within a year or two) or reach an equilibrium (chronic and permanent) state with no progression after that point. All have since been shown to be incorrect after recognition ofthe near-linear decline in CD4 counts over most of the period ofHN infection. 14o,141 The failure ofsuch a large variety ofthese early models suggests that some process unlike those employed when modeling other diseases is needed to successfully describe AIDS. In other words, something other than the HN-only theory is needed. A second example of the failure of a model is the idea of a diversity threshold,142 which tried to describe the role of the high mutation rate ofHN. Under this theory, the immune response can control an HN infection until the diversity threshold in the number of HIV quasi-species present is reached, at which time there are too many antigens for the immune response to deal with and the system begins to collapse. Although consistent with the understanding (the dots) at the time it was written, the theory was recognized as false with the recognition of the extraordinary scale ofthe diversity and the stable viral loads through most of the disease period. 143 The most direct demonstration that the HN-only theory may not be tenable is found in Anderson, Ascher, and Sheppard. 144 They demonstrate that even with the most generous of assumptions, the tap and drain view ofHN progression cannot be possible. The tap and drain model,1O,145,146 the current dogma, proposes that direct (cytopathic) killing ofCD4+ T cells by HN, which is slightly faster than normal homeostatic mechanisms can replace, is primarily responsible for the progression of HIV infection. The argument made by Anderson, Ascher, and Sheppard is that replacement is several magnitudes larger than any possible killing rate by HN-and that for most ofthe HN infection period, the virus cannot be shown to be cytopathic in vivo. Mechanisms and factors other than

HIV alone must be involved in the process. The authors mention several feasible hypotheses that are consistent with current data. Grossman et al 42 ,147 view the goal of the immune response to HN as primarily one of trying to come to terms with a chronic or parasitic infection. The deterioration or anergy (i.e., unresponsiveness) of the system arises from an "overadaptation of lymphocytes and accessory cells to the infectious agent(s)." Merrill and Radke 148 show that the linear decline in T cells and the distribution of the slopes of these declines are consistent with a slow decline ofimmune effectiveness as immune activation grows. Ascher and Sheppard 149,15o propose that T-cell signals generated by the interaction ofHN with CD4lead to excess immune activation, which results in a negative selection for CD4+ T cells. All three models contain a central role for pathology generated by an excess activation ofT cells. One way that activation enters this system is through cofactors, as previously discussed. The results of these epidemiological models make reasonable the hypothesis that cofactors are essential for the natural disease course seen in HN infection. That is, without externally supplied activation, the disease process cannot proceed. Root-Bernstein and Merti1l8 used a mathematical model to study the effects of cofactors in an HN infection. The results surprisingly suggest that if cofactors are absent, no infection by HN is possible if the dose of virus is small (e.g., a needle stick). Moreover, susceptibility to HN increases with increasing cofactor load,. Thus this model helps to explain the previous observation that people in different risk groups for HN infection seroconvert at different rates following a single HN exposure. If cofactors are necessary to the transmission ofHN, then those at highest risk ofinfection from a single exposure will be persons already immunologically compromised by a large number ofimmunological insults, whereas healthy individuals with low numbers ofactivated T cells and an insignificant antigen load should have a low susceptibility to HN. Another striking implication of the cofactornecessary model is that the nature of the AIDS epidemic becomes not a function of HN prevalence, but rather a complex function of the interaction of HN with cofactors. Thus HN may have existed at very low levels in human populations for hundreds or thousands of years before its recognition because the conditions for its widespread transmission did not exist. It is critical to realize that the HN epidemic followed

CHAPTER 2 Etiology and Pathogenesis of AIDS

closely behind epidemics of other sexually transmitted diseases and hepatitis viruses, as well as the innovation of disposable needles and syringes, vast increases in blood transfusions, and the use of blood-derived products. In a symbiotic or synergistic model, the effects of increasing these other factors would create a multiplicative effect on the incidence of HIV transmission, since people who acquired HIV would almost invariably also have the coinfections necessary to facilitate HIV transmission to others. 32 Conversely, medical and public health interventions that lower the cofactor incidence in a community will also have a multiplicative effect on lowering the incidence of HIV. Thus the efficacy of safer-sex measures and clean needle exchange programs may be due only partly to direct prevention of HIV exposure and, more importantly, to the concomitant intervention in the transmission ofcofactors necessary for HIV transmission. If this is true, then we should observe that the AIDS epidemic disappears in populations that lower their cofactor risks. Conversely, HIV will remain endemic among high-risk groups characterized by high levels of cofactor exposures.

IMPLICATIONS FOR RESEARCH, PREVENTION, AND TREATMENT Of the AIDS theories outlined in the first section of this chapter, two seem to be untenable. It is not likely that AIDS occurs in the absence of HIV. (This statement does not eliminate the possibility of acquiring significant immunosuppression in the absence ofHIV but suggests that such immunosuppression can be properly classified as something other than AIDS.) Conversely, no compelling evidence exists that HIV alone can produce AIDS. No individual who has developed AIDS has been shown to be free of putative cofactors, whereas the vast majority have been shown definitively to be exposed to putative cofactors. We are therefore left with some type of cofactor theory as the most likely explanation for AIDS. The problem is which type: (1) cofactor-modulated HIV or (2) cofactors-necessary HIV? Are we talking about a symbiotic interaction, synergistic interaction, or a progressive accumulation (antigenic overload) theory? Finally, what is the role of autoimmune processes in these theories? Are such processes an almost ubiquitous side effect of AIDS or one of its causes? At this time it is not possible to give a definitive answer to

43

these questions, in large part because the exclusive focus of the medical community on HIV has resulted in a general failure to see the many other processes that are part ofAIDS pathogenesis. Ignorance is not necessarily bad as long as it is recognized and carefully circumscribed. lSI In this instance, unanswered questions should become the springboards for future research. Laboratory and clinical investigators alike need to bear in mind the kinds ofstudies and data that will clarify outstanding questions. For example, very few studies exist correlating progression to AIDS with antigenic load as measured either by parameters of viral or bacterial antigens in blood or excretions, or by looking at general immune parameters. Despite data suggesting that CMV and EBV antigenemia are excellent markers for disease progression, no one has yet determined whether such viral antigen expression directly correlates with p24 HIV antigenemia or other HIV-derived correlates of AIDS development. Thus we have no idea whether HIV antigenemia precedes and stimulates the expression of other infectious agents or vice versa, or whether the two occur in tandem. A related issue concerns the systemic effects ofantiretroviral therapies. All current research assumes that the sole effect of such therapies is to lower HIV expression. Recently various nucleoside analogs designed to inhibit HIV replication have been found to inhibit the replication of cofactor viruses. Many nucleoside agents, including ddA, didanosine (ddI), and lamivudine (3TC), a common ingredient in antiretroviral cocktails, are extremely effective against hepatitis viruses and EBV.1l6.119 Conversely, ganciclovir and foscarnet, which were designed as anti-herpesvirus agents and used to treat CMV and genital herpes, significantly lower HIV antigen levels in treated patients. 114 Because many antiretrovirals are effective leukocyte inhibitors, all T-cell, macrophage, and dendritic cell infections might respond to such agents. If this is true (and it could easily be tested in the laboratory by looking at the effect of drugs on mixed infections in vitro), then it might make sense to change the selection criteria for novel AIDS therapies from those that are highly specific for HIV or particular cofactor viruses to those that are broadly effective against any immune system infection, including HIV. To accurately test any drug before it is used by human beings, however, it is necessary to establish viable animal models. Although AIDS models involving viruses analogous to HIV exist (e.g., simian

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immunodeficiency virus, feline immunodeficiency virus, murine immunodeficiency virus), significant differences also exist between human AIDS and these animal versions. Cofactor theories, whether they are synergistic, symbiotic, or progressive accumulation, suggest quite different and as yet untested animal models. No one has tested the effects of coinfecting chimpanzees and macaques, for example, with combinations of HIV, CMV, HTLV, and HHV-6, for example. No one has attempted to recreate in an animal exactly what happens to a human being who undergoes surgery, is exposed to multiple blood transfusions containing viruses such as CMV, EBV, and HCV, undergoes hours of anesthesia, and is given morphine, steroids, and other drugs postoperatively, in addition to encountering HIV. The effect of multiply exposing an animal anally to HIV contained in semen while the animal is simultaneously affected by antibiotics, nitrite inhalants, and various STDs (as occurred frequently in gay bath houses before the safe sex era) has never been reproduced. No one knows what effect chronic drug addiction, malnutrition, and multiple STDs has on the susceptibility of animals to HIV. Nor are these ludicrous experiments. It is worth considering that healthy rats, rabbits, and dogs are totally resistant to Candida albicans and P. carinii infections but become completely susceptible when immunosuppressed with steroids and other immunosuppressive agents.152.154 In addition, a new animal model for EBV infection has recently been discovered in rhesus monkeys, which may provide a means to investigate the interactions between EBVand HIV.155 Clearly some interventions can ethically be attempted on people at risk for AIDS even if such animal models are not developed. These include lifestyle interventions that lower the risk ofcontracting any putative cofactor and lessen the probability of infection following exposure to HIV and its development into AIDS. Therapies directed at cofactor infections or the elimination of ongoing immunomodulation factors, such as drug use and malnutrition, can also be implemented. Therapies that reduce cofactor risks without activating the immune system may be particularly useful. These may range from exercise, meditation, and counseling to drugs that mediate cytokine functions. Finally, since autoimmune diseases are virtually ubiquitous in AIDS patients, and since no effective treatments for any human autoimmune diseases exist, there is a possibility that even if clinicians learn how to control HIV and prevent retrovirally produced

immune dysfunction, most (if not all) people with AIDS will continue to die of untreatable autoimmune complications unrelated to immunosuppression. If autoimmunity is a major cause of immune dysfunction as well, then treatments designed to stop HIV may have little or no effect on long-term immunosuppression either. It is therefore crucial that the role of autoimmune processes in AIDS pathogenesis be clarified and a major effort made to determine the causes and treatments of the entire range of such processes. Such an effort would not only benefit hundreds of thousands of people with AIDS but millions of other people suffering from autoimmune diseases as well. It is worth remembering that AIDS itself is no more unique than any other disease. Whatever we know about disease in general must be applied to understanding and treating AIDS and, conversely, anything new we learn about AIDS and its effective treatment must be applied as broadly as possible to the understanding ofother diseases. Thus understanding AIDS will have far greater consequences than controlling AIDS; it may influence the paradigm by which we understand disease.

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Suggested Readings Al-Harthi L, Roebuck KA, Olinger GG, et al: Bacterial vaginosis-associated microflora isolated from the female genital tract activates HIV-l expression,] Acquir Immune Deftc Syndr 21:194-202,1999. Emery VC, Atkins MC, Bowen EF, et al: Interactions between beta-herpesviruses and human immunodeficiency virus in vivo: evidence for increased human immunodeficiency viral load in the presence of human herpesvirus6,] Med ViroI57:278-282, 1999. Grau 0, Tuppin P, Slizewicz G, et al: A longitudinal study of seroreactivity against Mycoplasma penetrans in HIV-infected homosexual men: association with disease progression, AIDS Res Hum Retroviruses 14:661-667, 1998.

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Hashemi FB, Ghassemi M, Roebuck KA, et al: Activation of human immunodeficiency virus type 1 expression by Gardnerella vaginalis,J Infect Dis 179:924-930, 1999. Hoffman IF, Jere CS, Taylor TE, et al: The effect of Plasmodiumfalciparum malaria on HIV-l RNA blood plasma concentration, AIDS 13:487-494, 1999. Kovacs A, Schluchter M, Easley K, et al: Cytomegalovirus infection and HIV-l disease progression in infants born to HIV-1-infected women, Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group, N EnglJ Med 341:77-84, 1999. Marino S, Kretschmer C, Brandner S, et al: Activation ofHIV transcription by human foamy virus in transgenic mice, Lab Invest 73:103-110, 1995. Otten MW Jr, Zaidi AA, Peterman TA, et al: High rate ofHIV seroconversion among patients attending urban sexually transmitted disease clinics, AIDS 8:549-553,1994.

Perez G, SkurnickJH, Denny TN, et al: Herpes simplex type II and Mycoplasma genitalium as risk factors for heterosexual HIV transmission: report from the heterosexual HIV transmission study. IntJ Infect Dis 3:5-11, 1998. Root-Bernstein RS: HIV and immunosuppressive cofactors in AIDS,J Immunol ImmunopharmacoI12:256-262. 1992. Semba RD, Kumwenda N, Hoover DR. et al: Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency vitus type I.J Infect Dis 180:93-98. 1999. Theus SA, Harrich DA, Gaynor R. et al: Treponema pallidum, lipoproteins. and synthetic lipoprotein analogues induce human immunodeficiency virus type 1 gene expression in monocytes via NF-kappaB activation,] Infect Dis 177:941-950, 1998. WardJW, Bush TJ, Perkins HA, et al: The natural history of transfusion-associated infection with human immunodeficiency virus, N EnglJ Med 321:947-968,1989.

Introdu,ction to Nutritional Approaches to HIV/ AIDS LEANNA J.

STANDISH

utrition is the most extensively researched of all the diverse areas of complementary and alternative medicine (CAM) in the treatment of HIV/ AIDS. This extensive research uses not only in vitro methods but also observational and clinical studies in HIV-infected humans. Numerous papers have been published studying the in vitro immunological and virological effects of single nutrients. Most of the human studies focus on measuring serum and cellular levels of nutrients, such as minerals, vitamins, and antioxidants, thought to be pertinent to HIV disease progress. Many studies suggest that the levels of important nutrients are lower in people infected with HIV and that these levels correlate with disease progression. I . 3

C)(

Results from several epidemiological studies suggest that deficiencies of certain nutrients, such as vitamin A, may be associated with a poor immune status and that higher intakes of micronutrients at baseline were associated with higher CD4 + T-cell counts. Longitudinal observational studies ofHIV-positive cohorts suggest that slowed disease progression is associated with an increased intake level of certain nutrients. Tang et al 4 conducted an epidemiological study of281 HIV-positive men, which provided evidence that certain dose ranges of dietary micronutrient intake ofvitamins BI , B2, B6, C, and niacin were associated with slowed disease progression, whereas high doses of zinc and vitamin A were associated with faster progression to AIDS. In another epidemiological study, Abrams

53

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AIDS AND COMPLEM ENTAR Y & AL TE RN ATIVE ME 0 I CI N E

prospectively examined the link between baseline dietary intake and development of AIDS in 296 HIVpositive men over a 6-year period. Higher intake of micronutrients at baseline was associated with higher CD4+ T-cell levels. In the same study, daily multivitamin use was associated with a reduced risk of AIDS and a reduced baseline risk oflow CD4+T-cell counts.s In 1996 Tang et al reported that intake of betacarotene at 2 times the required daily amount was associated with increased survival in HIV-positive persons. 6 The HIV Epidemiology Research Study (HERS) reported on correlates of nutritional status in a cohort of 626 women (426 HIV-positive, 199 HIV-negative). Among HIV-positive patients, higher levels of ferritin and lower levels of Bl2 , zinc (Zn), and selenium (Se) were associated with lower CD4+T-cell levels? Vitamin A deficiency was associated with lower CD4 + T-cell levels among both HIV-positive and HIV-negative intravenous drugs users (n = 179). Among HIV-positive subjects, vitamin A deficiency was associated with increased mortality.s Serum vitamin A appears to be related to vertical transmission rates of HIV infection in African women. Semba et al (1994) studied 300 HIVpositive mothers in Africa and found that the rate of transmission was much greater in women who had low vitamin A levels; rates ranged from 32% in the women with the lowest vitamin A levels to 7% in women with the highest levels. 9 Although the in vitro and epidemiological literature point to correlations between specific nutritional deficiencies, immunological status, progression, and transmission rates, it is uncertain if supplementation makes a positive difference. The current literature suggests that nutritional deficiencies are associated with decreased immune indices and higher risk for disease progression. The literature does not specify if additional supplementation above RDA levels increases immune indices or slows progression. A review of the literature elucidating how deficiencies of micronutrients, such as vitamin A, beta-carotene, Se, vitamin E, Zn, B vitamins, and magnesium (Mg), relate to clinical and laboratory measures of HIV disease illustrates the need for nutritional supplementation in HIV disease. 10-12 Since evidence of nutritional deficiencies in HIVinfected individuals exists, many clinicians and consumers in the HIV-infected community have concluded that oral administration of mega-doses of vitamins, minerals, and antioxidants, such as NAcetylcysteine (NAC), will slow progression of the dis-

ease. Surprisingly few human nutritional supplementation trials have been published. Controlled supplementation studies are needed to address whether oral supplementation of nutrients that are low in HIVinfected people or vitamins whose intake appears to be associated with slower disease progression in epidemiological studies significantly alters immunological status and viral load. Vitamin C, for example, is the most common alternative medicine reported by the Bastyr University AIDS Research Center's cohort of 1666 HIV-positive men and women. Yet vitamin C has not been evaluated in even a single clinical trial. Despite the fact that vitamin C is often taken in high doses by HIV-positive individuals, no controlled human studies have yet been done. Some in vitro research suggests that ascorbate can suppress HIV replication in both chronically and acutely infected T-cells. 13 With the exception of the effects ofvitamin A supplementation on HIV vertical transmission rates in pregnant women in Africa, the results of the few controlled clinical trials of single nutrients given in high oral doses to HIV-positive human subjects living in the United States have been disappointing. However, ample evidence from observational studies shows that even in US HIV-positive populations, vitamin and mineral supplementation is associated with decreased morbidity and mortality, although the relationships between some micronutrients and disease progression are complexly nonlinear. The next two chapters focus on the topic of nutritional approaches to HIV/AIDS, both written by key researchers in the field. Chapter 4 reviews nutritional deficiencies in AIDS patients and provides a sciencebased rationale for adjunctive nutritional therapy during all stages of HIV infection. Chapter 5 reviews the literature on antioxidant deficiencies in HIV-positive individuals and discusses the current literature on the effects of high-dose antioxidant supplementation on immune indices and disease progression.

References 1. Patrick L: Nutrients and HIV: part one-beta-carotene and selenium, Altern Med Rev 4(6):403-413, 1999. 2. Patrick L: Nutrients and HIV: part two-vitamins A and E, zinc, B vitamins, and magnesium, Altern Med Rev 5(1):39-51,2000. 3. Patrick L: Nutrients and HIV: part three-N-Acetylcysteine, alpha-lipoic acid, L-glutamine, and L-carnitine, A/· tern Med Rev 5(4):290-305,2000.

CHAPTER 3 Introduction to Nutritional Approaches to HIV/AIDS

4. Tang A, Graham NMH, et al: Dietary micronutrient intake and risk of progression to AIDS in HIV-l infected homosexual men, Am] Epidemiol138(11):937, 1993. 5. Abrams B, Duncan D, Hertz-Picciotto, I: A prospective study ofdietary intake and AIDS in HIV-seropositive homosexual men,] Acquir Immune Deftc Syndr Hum Retrovi· roI6(8):949-958, 1993.

6. Tang AM, Graham NM, Saah A]: Effects ofmicronutrient intake on survival in human immunodeficiency virus type 1 infection,Am] EpidemiolI43(12):1244-1256, 1996 (abstract We.B.182). 7. Smith, Graham, Flynn, et al: XI Int Con!AIDS ]u11996 (abstract We.B.182). 8. Semba RD, Graham NMH, Caiaffa WT, et al: Increased mortality associated with vitamin A deficiency during human immunodeficiency virus type 1 infection, Arch Intern Med 153:2149-2154,1993.

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9. Semba RD, Miotti PG, Chiphangwi]D, et al: Maternal vitamin A deficiency and mother-to-child transmission ofHIV-l, Lancet 343:1593-1597, 1994. 10. Patrick L: Nutrients and HIV: part one-heta-carotene and selenium, Altern MedRev4(6):403-413, 1999. 11. Patrick L: Nutrients and HIV: part two-vitamins A and E, zinc, B vitamins, and magnesium, Altern Med Rev 5(1):39-51,2000. 12. Patrick L: Nutrients and HIV: part three-N-Acetylcysteine, alpha-lipoic acid, L-glutamine, and L-carnitine, Altern Med Rev 5(1):290-305,2000. 13. Harakeh S,]ariwalla R], Pauling L: Suppression ofhuman immunodeficiency virus replication by ascorbate in chronically and acutely infected cells, Proc Natl Acad Sci USA 87:7245-7249, 1990.

Nutritional Deficiencies in AIDS Patients A Treatment Opportunity JEONGMIN KOZO

LEE

YOSHIKAWA

RONALD

ROSS

WATSON

ABSIRACT4mmune dysfunction resulting from infection with the human immunodeficiency virus (HIV) is a major health threat to populations in North America and throughout the world. Since HIVinfected persons in industrialized nations can survive a previously life-threatening infection through the use of effective medical therapies, malnutrition and wasting are becoming central issues in the health care plans of long-term survivors. Nutrition is a fundamental intervention in both the early and the ongoing treatment of HIV disease. Nutrition therapy, in coordination with other medical interventions, can extend and improve the quality and quantity of life in individuals infected with HIV and those living with acquired immune deficiency syndrome (AIDS).

9

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_ Medical nutrition therapy involves an assessment of nutritional status and treatment. Research on the relationship between nutrition and HIV infection is essential for understanding the mechanisms of wasting and for determining the effectiveness of medical nutrition therapy. This chapter uses currently published research papers to review the mechanisms and consequences of malnutrition in HIV/AIDS patients.

INTRODUCTION An individual's nutritional status influences morbidity and mortality (M&M) in many diseases, regardless of the disease process. Nutrition should be central in the

CHAPTER 4 Nutritional Deficiencies in AIDS Patients

treatment of HN infection because of the chronic nature of HN and the numerous related opportunistic infections (DIs) that affect the digestive tract. Because undernutrition adversely affects immune defenses in people who do not have HIV, nutritional deficiencies in HIV-infected people accelerate the development of severe immunodeficiency. Although it has been poorly studied, nutritional supplementation may therefore overcome nutritional deficiency and immunosuppression in AIDS. Recently vitamin E deficiency was identified in HN-infected people. I Another study showed that vitamin E replacement slowed the development of immune deficiency.2.3 An associated editorial concluded that more research is needed on the benefits of vitamin supplementation to slow the loss of immune defenses and promote well-being in HN-infected persons and that supplementation should start now while research is underway.4 Therefore we reviewed vitamin and mineral deficiencies in AIDS patients and concluded that they are prevalent and should be treated, since they accentuate immune damage. A macronutrient deficiency such as wasting, a common occurrence in HIV disease, is a proteincalorie malnutrition and is caused by inadequate calorie and protein intake, absorption, or use. The resulting loss of weight and muscle mass is directly associated with a deterioration in health and increased mortality. The loss oflean body mass (LBM) is associated with a greater incidence of DIs, further deterioration in immune function, and poorer nutritional status. s Because malnutrition has a direct impact on immune function, maintaining the nutritional status of the HIV-infected patient is a central concern.

MACRONUTRIENT DEFICIENCY AND PROGRESSION TO AIDS Energy Expenditure Resting energy expenditure (REE) correlated positively with the presence of HIV infection. REE was 10% higher in stable HIV-positive subjects and AIDS patients than in healthy controls. 6.7 Grunfeld found that REE was higher in HN-positive patients, AIDS-related complex (ARC) patients, and AIDS patients who did not have concomitant DIs than it was in healthy controls, as long as the patient's oral intake was sufficient to maintain body weight (BW).8 This finding contrasts

57

with AIDS patients who had concomitant infections, which resulted in increased REE, decreased oral intake, and weight loss. There was no compensatory decrease in REE, as might be expected with decreased oral intake. Failure to regulate REE as an adaptation to anorexia or malabsorption is often stated as the major cause of weight loss in individuals with AIDS. However, total energy expenditure (TEE) in HIVinfected patients was not significantly different from that in healthy controls but was decreased slightly in weight-stable AIDS patients. 6 With a spectrum ofREE for hospitalized ARC and AIDS patients without malabsorption or uncontrolled infection,9 6% were hypometabolic, 26% were normal-metabolic, and 68% were hypermetabolic. Hypermetabolism is characteristic ofcachexia (i.e., muscle wasting, inefficient use of energy, and loss of LBM), as seen in cancer and other chronic disease states, whereas hypometabolism is an appropriate compensatory response to starvation and protein-energy malnutrition. It is unclear ifweight loss correlates with the metabolic rate, since some studies show a decrease in energy expenditure during periods of weight loss.8.10 Although REE increased in HIV-positive and AIDS patients, changes in weight correlated not with REE but with caloric intake. 8 The most common physiological causes of hypermetabolism, such as pregnancy, adolescence, and exercise, do not usually lead to wasting, perhaps because of higher caloric intake and metabolic adaptation. I I The etiology of possible hypermetabolism remains unclear, since increased hormones or tumor necrosis factor (TNF) were not found in patients with high REE. 12.13 Whether or not chronic hypermetabolism occurs, frequent fevers associated with secondary infections in HIV-infected patients may result in short-term increased REE.5 Malignancy may also raise REE.14 It is, however, unclear if hypermetabolism is sufficient to cause wasting in the absence of other processes, although hypermetabolism may occur in some HN-infected patients. I I

Body Weight and Composition Body wasting, particularly loss of body cell mass (BCM), is an increasingly prevalent AIDS-defining condition and is an independent risk factor for death in HIV-infected patients. Although they had the same BWas the controls, HIV-positive male patients had less BCM, greater potassium depletion,

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less intracellular water, more extracellular water, decreased serum proteins (e.g., albumin, retinolbinding protein [REP]), and decreased total iron binding capacity (TIBC). This depletion occurred to a greater extent in the patients with diarrhea. Compared with normal values, body fat was also depleted but was similar to that of a control group of healthy homosexual males. Loss of body fat was found even in the earlier stages of HIV infection and was more severe than loss of BCM. Female patients had a larger decrease in body fat than male patients, whereas males showed a greater relative depletion ofBCM than body fat. In more stable ambulatory patients with AIDS, however, weight loss was not associated with reductions in LBM, body fat, or total water, and the explanation for weight loss was unclear. 15 In a follow-up retrospective study of wasted AIDS patients during the 100 days before death, BCM (decreased 50%) was reduced out of proportion to weight loss (decreased 33%).16 In patients who died within 100 days of a body composition measurement, those with the lower BCM died sooner. Specifically, a loss of 37% of BW was associated with death. This study revealed that the progression of wasting was independent of body fat changes but was associated with loss ofBCM. Thus a patient could have a normal BW yet a low BCM and still be at risk for death due to malnutrition.

Pathophysiology of Malnutrition in HIV Disease A number of possible etiologies of weight loss in HIV infection exist. HIV wasting syndrome also may be multifactorial in etiology.17 Multiple etiologies may be present in a single patient. The most likely etiologies can be divided into the broad categories of (1) decreased food intake, (2) malabsorption, (3) alterations in metabolism, (4) cytokine effects, (5) endocrine dysfunction, (6) steroids and growth hormones, (7) primary muscle disease, and (8) alcohol abuse.

Decreased Food Intake Decreased food intake may result from anorexia or nausea secondary to medications, systemic illness (mediated by cyrokines), neurological disease, or oral or esophageal pathology (e.g., dry mouth, odynophagia, ulcers, or malignancy).IB Taste and smell loss due to medications, oral pathology such as candidiasis, and peripheral or

central nervous system (CNS) disease are well documented in HIV-infected patients. These chemosensory abnormalities can impair food intake and contribute to wasting. Additionally, fatigue, dementia, and peripheral myoneuropathies influence a patient'S ability to obtain food. Monetary considerations also playa role. Dependence on other people to prepare or purchase food may also limit a debilitated patient'S intake.

Malabsorption Oral, esophageal, stomach, pancreatic, biliary, hepatic, and small and large intestine pathology can influence the absorption ofnutrients. Malabsorption, chronic diarrhea, or both may be secondary to infections, malnutrition, medications, enzyme deficiencies, malignancies, and HIV enteropathy.19 Diarrhea is found in over 50% of AIDS patients with pathogens, including Cytomegalovirus, herpes simplex virus, adenovirus, Sal-

monella, Shigella, Campylobacter, Clostridium difficile, Mycobacterium avium-intracellulare, Giardia, Entamoeba, Cryptosporidium, Microsporidium, and Isospora. 19 Gastrointestinal dysfunction, especially malabsorption, is prevalent in advanced HIV infection, with or without identifiable pathogens. Villous abnormalities are frequent in these HIV-infected individuals, and small intestinal dysfunction has been demonstrated by abnormal D-xylose absorption tests, Schilling tests, C-14 glycocholate absorption, and the presence ofsteatorrhea. l3 ,2o Small intestinal pathology or pancreatic insufficiency may lead to fat malabsorption, weight loss, and depletion of fatsoluble vitamins in HIV-infected persons. Fat malabsorption occurred in 48% ofa range ofHIV-infected patients using a C-14 triolein breath test. 21 Although severe malabsorption is limited to patients who have advanced HIV disease with CD4 + T-cell counts <100 and usually <50 cells/ml, overt malabsorption has not been described in early HIV infection. However, studies indicate that subclinical malabsorption may playa role in early HIV disease without evidence of diarrhea. The D-xylose test was abnormal in 25% of patients with early HIV disease,22 and the lactulose mannitol permeability test was abnormal in 16%.23 In addition, the hypometabolic status and reduced glucose cycling in clinically stable AIDS patients could be explained by subclinical malabsorption. 15 ,24 Hypochlorhydria has been found in 74% of AIDS patients25 and is a permissive factor for enteric infections and bacterial overgrowth of the small intestine. 26 Furthermore, hypochlorhydria de-

CHAPTER 4 Nutritional Deficiencies in AIDS Patients

creased the absorption ofcertain micronutrients such as folate and ironP Lactase or other disaccharidase deficiency has also been reported in AIDS patients.

Altered Metabolism Evidence exists for both hypermetabolism and hypometabolism in HIV-infected patients. The cachexia associated with cancer or concomitant inflammation has been related to the production ofTNF.28 Therefore the cachexia that occurs in HIV-positive persons also may be related to excess TNF production. This hypothesis has not yet been proven. Another study showed enhanced TNF production from peripheral blood mononuclear cells (PBMCs) of healthy subjects who had been starved for 6 days.29 The intricate relationship between cytokine production, metabolic disturbances, viral burden, and weight loss in HIVinfected individuals is not completely understood. Increased futile cycling of substrates, energy use, and heat production exist without a net gain in product (such as fat oxidation and synthesis, triglyceride hydrolysis, and reesterification). In murine AIDS lipid levels in tissues and oxidation increase significantly.3o Cytokine production also has metabolic consequences. For example, TNF enhances hepatic lipogenesis and very low density lipoprotein (VLDL) release, inhibits adipocyte lipoprotein lipase, and enhances adipocyte lipolysis. The result is that fatty acids (FAs) mobilize peripherally to the liver to be made into VLDLs and circulate but are not stored or used for energy. Other cytokines (e.g., IL-!~, IL-6, IFN-n, and IFN-'Y) may synergize with TNF to enhance this cycle, as well as glucose futile cycles and proteolysis. This results in cachexia. Synergistic interactions are especially important during secondary OIs in HIV-positive persons. Studies regarding basal blood levels of TNF, IL-!~, and IFN-n in HIV-positive patients are conflicting. 31 Wasting has not been directly proportional to circulating blood levels of triglycerides, free FAs, TNF, or IL-!~.32 However, levels of IFN-n correlate positively with serum triglycerides. 33 TNF and IL-! are produced by PBMC and monocyte cell lines infected in vitro with HIV-! or PBMC isolated from HIV-positive patients. 34 Some researchers speculate that increased TNF production is related to the stage of disease; PBMC from patients with ARC or AIDS produce more TNF than those from patients with an asymptomatic infection. 35

59

Cytokines Elevated levels of certain cytokines, particularly TNF, may be responsible for the wasting and weight loss seen in AIDS patients. 36,37 However, several studies report elevations ofTNF, particularly in symptomatic patients, while others do not. 38 ,39 In murine AIDS there is a significant increase in circulating TNF and TH2 cell cytokines such as IL-6 but no change in muscle mass. 40 In a group of 33 HIV-positive outpatients, elevated TNF levels did not correlate with weight loss or increased metabolic rate. 41 Serum assays ofTNF often are not sensitive or accurate enough to detect elevations, particularly since TNF is secreted in a pulsatile fashion. 38,39 Either TNF or other cytokines could cause weight loss or HIV wasting syndrome by a number of mechanisms. TNF, and possibly IL-!, may induce anorexia. Alternatively, TNF may affect lipid metabolism, leading to a relative decrease in fat oxidation compared with carbohydrate or protein oxidation and a relatively greater loss ofLBM.42 The effect ofTNF on AIDS patients may depend on its site of production. For example, intracerebral TNF-secreting tumors produced lethal anorexia and weight loss in mice with relative sparing of protein-a model of starvation. 43 TNFsecreting tumors in peripheral muscle tissue resulted in much slower cachexia with a greater loss of protein. 43 A variety of other potential mechanisms of TNF action have been discussed. 44 Some investigators suggest that the interaction ofTNF with other cytokines, such as IL-!, or with other inflammatory mediators may induce anorexia, accelerated protein breakdown, or wasteful energy expenditure. 38 ,42

Endocrine Abnormalities Endocrine dysfunction is another possible etiology of HIV wasting syndrome. Endocrine abnormalities in HIV-infected patients, including changes in gonadal, adrenal, and thyroid function, occur frequently and could lead to weight loss and wasting. 39 ,44 Low levels of reverse triiodothyronine (rT3) and a persistence of triiodothyronine (T 3 ) within the normal range 45 mark HIV infection. This finding is consistent with most severe infections, in which rT3 rises and T 3 falls. Normal serum T 31evels may be an inappropriate response to the caloric deprivation of normal illness or result from a cytokine effect, and they might result in continued high energy expenditure leading to weight 10ss.45 TNF and IL-! have been shown to cause an

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A ( 0 SAN 0 COM P L E MEN TAR Y & A LT ERN A T I V E M E 0 I C I N E

inappropriately normal T3 and a low rT3 state in mice and appear to stimulate the enzyme iodothyronine 5'-deiodinase (5'D), which results in increased synthesis ofT3 from T 4 and increased degradation of rT3,46 However, other studies suggest that serum T 3 falls appropriately in the presence of AIDS and acute 0ls,44 Adrenal insufficiency in AIDS has been reported occasionally, often stemming from Ols or the effects of medication,47 Some patients had a suboptimal cortisol response to the administration of adrenocorticotropic hormone (ACTH) and conceivably could develop clinical adrenal insufficiency during acute infection. 47 The basal cortisol levels are elevated in patients with HIV compared with controls. 48 Elevation in cortisol levels can be a physiological response to severe weight loss as the body attempts to maintain glucose hemostasis in the brain. Decreased testosterone and dehydroepiandrosterone (DHEA) have been reported in a number of studies of HIV-infected men,44,49 DHEA and DHEA sulfate (DHEAS) are sterols that are synthesized from cholesterol in humans, DHEAS is water soluble and easily transported by attaching to albumin, It is present in humans at 1000 times the level of DHEA and functions as a inactive reservoir. Because DHEA and DHEAS interconvert, DHEAS often converts to DHEA; however, the conversion ofDHEA to DHEAS is much less frequent, DHEA can be converted in tissues to more potent androgens, testosterone, and dihydrotestosterone. It acts as an estrogen as well. DHEA levels and CD4+ T-cell counts decline in HIVinfected people. We showed that DHEA supplementation prevented most of the immune dysfunction, cytokine dysregulation, and loss of nutrients during murine AIDS,50 Lowered levels of testosterone are correlated with weight loss and decreased survival. 44 In a study of patients with HIV wasting syndrome, free and total testosterone was significantly lower in patients with similar CD4 + T-cell counts but without wasting. 44 Since testosterone is an anabolic hormone, a deficiency could result in decreased LBM and contribute to HIV wasting syndrome.

Steroids and Growth Hormone If BCM does not increase rapidly despite improved energy intake, anabolic pharmacological approaches may be used to augment nutritional intervention. Because severe loss ofBW is directly associated with risk of death and lower survival rates in end-stage AIDS,

replacement testosterone therapy should be initiated early.51 Recent studies report marked gains in LBM from administration of anabolic steroids. An open study of nandrolone decanoate (100 mg/ml), intramuscularly (1M) administered every 2 weeks for 16 weeks, enrolled 24 patients with HIV infection who had lost 5% to 15% of their usual BW,52 The study found that nandrolone decanoate resulted in marked increases above baseline in BW, LBM, and quality oflife (QOL), Another study spanning 8 weeks with 24 HIV-infected men reported that 1M testosterone and oxandrolone (20 mg/day) resulted in considerable increases in LBM, BW, and strength compared with treatment using 1M testostetone and a placebo,53 However, clinical trials providing more data and a larger number of patients are needed in this study before recommendations can be made regarding the inclusion of anabolic steroids in wasting therapy. Another study of oxandrolone (15 mg/day) reported a marked weight increase above baseline compared with placebo-treated patients who lost weight. Growth hormone (GH) deficiency is postulated to be a possible cause of HIV wasting. AIDS wasting is associated with a GH-resistant state that results in low levels of serum insulin-like growth factor 1 and 2 (IGF-l, IGF-2), IGF-binding protein 3 (IGFBP-3), elevated levels of phosphorylated IGF-binding protein 1 (IGFBP-l), and a reduced ability to form the IGFBP-3 ternary complex. 54 AIDS patients who lost more than 10% of their ideal body mass demonstrated a 50% reduction in serum IGF-l and a 70% reduction in IGF-2 compared to healthy HIV-negative subjects. The wasting syndrome of rabies infection is found to cause pituitary and hypothalamic dysfunction, resulting in decreased growth hormone production,55 It is possible that a similar mechanism may occur in AIDS, Recent studies have shown beneficial effects ofGH therapy on LBM, muscle mass, and protein synthesis, A relatively large, double-blind, and placebo-controlled study of recombinant human GH (rhGH) with 178 HIV-infected patients demonstrated that 0,1 mg/kg of rhGH/day induces statistically significant weight gain, accrual of LBM, increased strength, and loss of body fat over 12 weeks of treatment,56 In a study ofsix AIDS patients, 0.1 mg/kg of rhGH was shown to induce positive nitrogen balance and a retention of BCM, implicating that adding exogenous rhGH overcomes the acquired GH resistance in these patients,57 In both studies, GH was well tolerated in AIDS

CHAPTER 4 Nutritional Deficiencies in AIDS Patients

patients. Most adverse effects were mild to moderate and included tissue edema, pain, arthralgia, and myalgia. These adverse symptoms generally responded to a reduction in the dose of rhGH. The mechanism ofaction ofGH in AIDS is unclear. However, some possibilities have been explored in recent years. GH can induce thymic hyperplasia and the generation of new CD4 + T cells in mice, and IL-7 may be the effector molecule promoting thymopoiesis. 58 In addition, GH potentiates the proliferation and cytokine responses of human antigen-specific CD4 + helper T and CD8 + cytotoxic T-cell clones to their antigens. 59 GH improves the ability of dendritic cells to present a cognate antigen and provide costimulation at a maximal concentration of 10-50 lJ.g/m1. 60 Regardless of the beneficial effects of GH in AIDS patients, limitations still exist. The cost of GH as a long-term therapeutic reagent is a concern. Therefore researchers have explored the effectiveness of shortterm use of GH. A recent study reported that a shortterm intervention with rhGH prevents weight loss during acute OIs in patients with AIDS.61 Another potential concern is the adverse effects of GH therapy, such as mild edema, arthralgia, and possible tumor cell proliferation. 56 Thus after the patient has tried GH therapy, a progress assessment is recommended. In addition, other measures of disease progression, such as CD4 + T-cell count and viral load, should be monitored to ensure that no intervening clinical events have occurred. Continued nutritional support and assessment are also required.

Primary Muscle Disease HIV wasting syndrome may result from a myopathy. Myopathy may occur as a complication of HIV-I infection or from its treatment, zidovudine (AZT). No evidence exists to support a direct retroviral etiology. HIV-associated myopathy more likely has an immunemediated pathogenesis. HIV antigens are localized in macrophages invading muscle, suggesting a role for virus-infected inflammatory cells in muscle degeneration. 62 The lack of significant inflammation in many of the muscle biopsies of individuals who have HIV wasting syndrome may reflect their profound immunological impairment. 5% of patients with HIV wasting syndrome had myopathy by clinical, laboratory (e.g., creatinine kinase and electromyelogram [EMG]), and muscle biopsy criteria. 63 Among these patients, prednisone caused decreases in creatinine kinase and increases in strength. The connection ofAZT

61

and HIV to myopathy and loss of muscle mass requires further evaluation.

Alcohol Abuse Progression from HIV infection to AIDS took a few months in people consuming large amounts of alcohol instead of the expected 7 to 11 years. 64 Greatly increased alcohol use stimulated HIV replication, suppressed immune defenses, and promoted progression to AIDS.65 Heavy alcohol use is common among intravenous (IV) drug users. The relative risk of AIDS was 3.8 times higher in heavy alcohol drinkers than in moderate ones. 66 Alcohol abuse was more common among AIDS patients than among HIV-infected drug abusers 66 or uninfected IV drug users. A study involving heavy alcohol drinkers who were HIV-infected showed a 41%increase in CD4 + T cells after cessation ofalcohol use,67 whereas only a 15% increase was seen in uninfected controls who quit drinking. Such changes suggest that the potential direct (i.e., immunotoxic) actions of heavy alcohol use, as well as indirect ones due to undernutrition, by HIV-infected people result in a 30% to 40% decrease in CD4 + T cells over a 4-year period. 67 We documented the effects of alcohol consumption in murine AIDS.68,69 Alcohol accentuated the loss of disease resistance due to retrovirus infection even when ethanol consumption had no effect on disease resistance in uninfected mice. 69 ,70 Thus alcohol acted as a cofactor, which was sufficient for accelerated development of murine AIDS. In our murine AIDS model, alcohol consumption exacerbated cytokine dysregulation,68 increased immune dysfunction,71 and further suppressed disease resistance to pathogens common in AIDS patients. 69 ,70 Although alcohol use in mice who did not have retroviral infection had some effects on cytokine production and immune dysfunction,n it was not sufficient to significantly suppress disease resistance to AIDS-associated pathogens. 73 Alcohol use before retroviral infection in mice was sufficient to accelerate development ofsevere murine retroviral immunosuppression.74 Oxidation causes DNA damage to lymphocytes, whereas supplementation with vitamin E, vitamin C, or beta-carotene greatly reduces the DNA damage in lymphocytes of both smokers and nonsmokers. 75 Serum antioxidants (e.g., a-tocopherol, retinol, betacarotene, glutathione, selenium, zinc) in alcoholics decreased significantly. Since alcohol and retrovirus infection each induce losses in tissue antioxidants, they

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should promote greater DNA damage and dysfunction in lymphocytes when used together. Reduction of immunostimulatory antioxidants by alcohol abuse is accentuated by retrovirus infection. Micronutrient deficiencies should synergize with HIV immunosuppression to increase immune dysfunction and accelerate progression to AIDS.

all HIV-infected persons. The most likely mechanism for the beta-carotene deficiency is related to impairment of free radical (FR) elimination and failure to protect cellular membrane against lipid peroxidation (LP), including damage to CD4 + T cells. 81 Consequently, beta-carotene deficiency, along with other antioxidant deficiencies, may contribute indirectly to the immunological deterioration seen in HIV infection by facilitating CD4 + T-cell apoptosis.

MICRONUTRIENT DEFICIENCY AND PROGRESSION TO AIDS Vitamin A Progressively decreased serum vitamin A levels in HIV-infected patients are associated with increased M&M. Low levels among pregnant women with HIV are related to low birth weight (LBW), higher maternal and infant mortality, and increased mother-tochild transmission ofHIV,76,77 The biological mechanisms by which vitamin A deficiency could influence mother-to-child transmission of HIV-l include impairment of immune responses in both mother and infant, abnormal placental and vaginal pathology, and increased HIV viral burden in breast milk and blood. A number of possible causes oflow serum vitamin A levels exist, including (1) decreased dietary intake, (2) poor gastrointestinal (GI) absorption, (3) high urinary losses, (4) impaired hepatic protein synthesis, and (5) increased nutritional demands related to chronic infection,78 Most dietary vitamin A is delivered to the liver and released into the blood to be used by peripheral tissues. The synthesis and release of serum carrier protein and RBP regulate this action. Thus impaired RBP synthesis or release may lead to low serum vitamin A levels despite adequate dietary vitamin A and adequate stores in the liver. However, serum vitamin A levels are also highly correlated with RBP in people who are not infected with HIV, suggesting that this correlation does not indicate impaired hepatic protein synthesis. 79 HIV-infected patients are most concerned about whether vitamin A supplementation will increase survival and reduce mother-to-child transmission ofHIV. HIV-infected patients taking supplemental vitamin A had significantly higher serum vitamin A levels and higher RBP levels than those not taking vitamin A. Moderately high intake of vitamin A slowed progression to AIDS.8o Serum beta-carotene concentration is deficient in

Vitamin B6 Vitamin B6 plays a critical role in nucleic acid and protein metabolism; thus a deficiency significantly alters immune responses. 82 The prevalence ofvitamin B6 deficiency in HIV-infected patients ranges from 12% to 52%.83 Vitamin B6 deficiency also results in the impairment ofboth cell-mediated and humoral immune responses, including impaired IL-2 production and lymphocyte proliferation in response to mitogens in uninfected animals and people. 84 In HIV-infected persons vitamin B6 causes delayed cutaneous hypersensitivity, depressed cell-mediated immune response, depressed lymphocyte proliferation, decreased CD4 + T-cell counts, and reduced natural killer (NK) cell cytotoxicity.83,85 Vitamin B6 repletion with coenzyme QIO increases IgG, CD4 + T cells, and the ratio of CD4 +/CD8 + lymphocytes in uninfected older people and animals. 86 These increases may be clinically important to accelerate progression to AIDS, suggesting a role for vitamin B6 supplementation in the treatment of nutritional immunodeficiency.

Vitamin B 12 A significant number ofelderly and HIV-positive individuals are at increased risk ofvitamin B12 deficiency.87 Decreased serum vitamin B12 levels occur in up to 20% of patients with early-stage AIDS.88 DeVelopment of vitamin B12 deficiency is associated with a decline in CD4 + T-cell counts and a number of neurological and neuropsychiatric disorders. Neurological damage caused by vitamin B12 deficiency may be due to methyl group deficiency as a result of either the patient'S inability to synthesize methionine and S-adenosyl-Lmethionine (SAM) or the toxicity of homocysteine accumulation.89 Low serum levels of haptocorrin in HIVI-positive patients could also lead to the low levels of

CHAPTER 4 Nutritional Deficiencies in AIDS Patients

serum vitamin Bu frequently observed in this patient population. In some cases subnormal serum vitamin BI2 levels adversely contribute to the hematological and neurological dysfunction attributed to HIV.90 Decreased levels of vitamin B12 are also highly prevalent in HIV-infected patients with chronic diarrhea. Low serum vitamin BI2 concentrations are more closely associated with faster HIV-l disease progression and a decline in CD4+T-cell counts than are low vitamin B6 concentrations. 91 Metabolic and clinical disturbances due to decreased serum vitamin B12 1evels lowered hemoglobin, leukocytes, and the ratio of CD4 +/CD8+ T-cell counts in HIV-infected patients compared to those in HIV-infected patients with normal serum vitamin B)2 levels. Thus disease progression to AIDS may be predicted by the change in serum vitamin B12 levels and CD4+T-cell counts and might be slowed by vitamin BI2 supplementation.

Vitamin E Plasma concentration ofvitamin E is less significantly decreased than that of vitamin A in HIV-infected patients. Vitamin E deficiency is found mostly in patients who have wasting syndrome. 92 Thus low plasma vitamin E levels could be related partly to dietary intake or absorption, suggesting that supplementation may be warranted in HIV-1-infected persons with a vitamin E deficiency. In contrast, circulating vitamin E levels decrease considerably in HIV-positive patients after progression to AIDS.93 Vitamin E levels are four to five times higher in lymphoid cells than in other cells. Since vitamin E is an antioxidant of cell membranes and plasma lipoproteins, a deficiency of vitamin E is related to the increase ofLP. Paradoxically, LP is more significant in asymptomatic HIV-negative patients than in AIDS patients. 94 In early HIV-1 infection, the elevation of plasma IgE levels precedes the decline ofCD4+ T-cell counts and is influenced by vitamin E status. 92 Recently HIV-infected people were shown conclusively to lose vitamin E as progression to AIDS occurred. 92 Supplementation with vitamin E slowed this process,93 and an editorial called for more trials and supplementation of HIV-infected persons. 94 These conclusions are supported by animal model studies. In one animal model, C57BL/6 mice were infected with an LP-BM5 retrovirus causing murine AIDS. Extremely high levels ofvitamin E supplementation significantly normalized the levels ofIL-2, IL-6,

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IL-10, IPN·'Y, and TNF-ex produced by a splenocyte. 95 Vitamin E supplementation at 15 to 450 times the